Six months ago, researchers at UCLA published a study that showed using a specific type of yoga to engage in a brief, simple daily meditation reduced the stress levels of people who care for those stricken by Alzheimer’s and dementia. Now they know why.
As previously reported, practicing a certain form of chanting yogic meditation for just 12 minutes daily for eight weeks led to a reduction in the biological mechanisms responsible for an increase in the immune system’s inflammation response. Inflammation, if constantly activated, can contribute to a multitude of chronic health problems.
Reporting in the current online edition of the journal Psychoneuroendocrinology, Dr. Helen Lavretsky, senior author and a professor of psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior, and colleagues found in their work with 45 family dementia caregivers that 68 of their genes responded differently after Kirtan Kriya Meditation (KKM), resulting in reduced inflammation.
Caregivers are the unsung heroes for their yeoman’s work in taking care of loved ones that have been stricken with Alzheimer’s and other forms of dementia, said Lavretsky, who also directs UCLA’s Late-Life Depression, Stress and Wellness Research Program. But caring for a frail or demented family member can be a significant life stressor. Older adult caregivers report higher levels of stress and depression and lower levels of satisfaction, vigor and life in general. Moreover, caregivers show higher levels of the biological markers of inflammation. Family members in particular are often considered to be at risk of stress-related disease and general health decline.
As the U.S. population continues to age over the next two decades, Lavretsky noted, the prevalence of dementia and the number of family caregivers who provide support to these loved ones will increase dramatically. Currently, at least five million Americans provide care for someone with dementia.
“We know that chronic stress places caregivers at a higher risk for developing depression,” she said “On average, the incidence and prevalence of clinical depression in family dementia caregivers approaches 50 percent. Caregivers are also twice as likely to report high levels of emotional distress.” What’s more, many caregivers tend to be older themselves, leading to what Lavretsky calls an “impaired resilience” to stress and an increased rate of cardiovascular disease and mortality.
Research has suggested for some time that psychosocial interventions like meditation reduce the adverse effects of caregiver stress on physical and mental health. However, the pathways by which such psychosocial interventions impact biological processes are poorly understood.
In the study, the participants were randomized into two groups. The meditation group was taught the 12-minute yogic practice that included Kirtan Kriya, which was performed every day at the same time for eight weeks. The other group was asked to relax in a quiet place with their eyes closed while listening to instrumental music on a relaxation CD, also for 12 minutes daily for eight weeks. Blood samples were taken at the beginning of the study and again at the end of the eight weeks.
“The goal of the study was to determine if meditation might alter the activity of inflammatory and antiviral proteins that shape immune cell gene expression,” said Lavretsky. “Our analysis showed a reduced activity of those proteins linked directly to increased inflammation.
“This is encouraging news. Caregivers often don’t have the time, energy, or contacts that could bring them a little relief from the stress of taking care of a loved one with dementia, so practicing a brief form of yogic meditation, which is easy to learn, is a useful too.”
Lavretsky is a member of UCLA’s recently launched Alzheimer’s and Dementia Care Program, which provides comprehensive, coordinated care as well as resources and support to patients and their caregivers. Lavretsky has incorporated yoga practice into the caregiver program.
Funding for the study was provided by the Alzheimer’s Research and Prevention Foundation in Tucson, Ariz.. Other authors of the study included David S. Black, Steve Cole, Michael R. Irwin, Elizabeth Breen, Natalie M. St. Cyr, Nora Nazarian, all of UCLA, and Dharma S. Khalsa, medical director for the Alzheimer’s Research and Prevention Foundation in Tucson.
Eliminating the PSA test to screen for prostate cancer would be taking a big step backwards and would likely result in rising numbers of men with metastatic cancer at the time of diagnosis, predicted a University of Rochester Medical Center analysis published in the journal, Cancer.
The URMC study suggests that the prostate-specific antigen (PSA) test and early detection may prevent up to 17,000 cases of metastatic prostate cancer a year. Data shows, in fact, that if age-specific pre-PSA era incidence rates were to occur in the present day, the number of men whose cancer had already spread at diagnosis would be three times greater.
“Our findings are very important in light of the recent controversy over PSA testing,” said Edward M. Messing, M.D., study co-author, chair of Urology at URMC, and president of the Society of Urologic Oncology. “Yes, there are trade-offs associated with the PSA test and many factors influence the disease outcome. And yet our data are very clear: not doing the PSA test will result in many men presenting with far more advanced prostate cancer. And almost all men with metastasis at diagnosis will die from prostate cancer.”
Prostate cancer usually occurs in older men, and is the second leading cause of cancer death in the male population. In 2012 an estimated 241,740 new cases will be diagnosed and 28,000 deaths will occur. Prognosis depends on whether the cancer has spread outside the prostate gland, and the degree to which the cancer cells are abnormal.
In 2011 the U.S. Preventive Services Task Force recommended against PSA screening in all men, prompting criticism from the medical community. The government panel reviewed scientific evidence and concluded that screening has little or no benefit, or that the harms of early detection outweigh the benefits. One major concern, for example, was that doctors are screening for, finding, and treating non-aggressive cancers that might have remained quiet, causing patients to needlessly suffer from serious treatment side effects such as incontinence or erectile dysfunction.
The U.S. Task Force recommendations against screening caused some confusion, and in response, a special panel of experts from the American Society of Clinical Oncology issued its own opinion. The ASCO panel decided that for men with a life expectancy of less than 10 years, general screening with the PSA test should be discouraged. For men with a longer life expectancy, though, it is recommended that physicians discuss with patients whether the PSA test is appropriate for them.
Messing’s study looked back at the era prior to 1986, when no one was routinely screened for prostate cancer with a PSA test. To analyze the effect of screening on stage of disease at initial diagnosis, Messing and Emelian Scosyrev, Ph.D., assistant professor of Urology, reviewed data from 1983 to 2008 kept by the nation’s largest cancer registry, Surveillance, Epidemiology and End-Results or SEER. They compared SEER data from the pre-PSA era (1983 to ’85) to the current era of widespread PSA use (2006 to 2008), and adjusted for age, race, and geographic variations in the United States population.
Approximately 8,000 cases of prostate cancer with metastases at initial presentation occurred in the U.S. in 2008. Using a mathematical model to estimate the number of metastatic cases that would be expected to occur in 2008 in the absence of PSA screening, Scosyrev and Messing predicted the number would be 25,000.
The authors emphasized the study was observational and has some limitations. In particular it is impossible to know if the PSA test and early detection is solely responsible for the fewer cases of metastasis at diagnosis in 2008.
The potential lead-time of screening also should be considered when interpreting the study findings, Scosyrev said. For some people an earlier stage of cancer at diagnosis may not always translate into better survival. This may happen, for example, in cases when the cancer had already metastasized at the time of screening, but the metastasis remained undetected.
In general, however, the study concluded that massive screening and PSA awareness efforts during the 1990s and early 2000s resulted in substantial shifts toward earlier-stage disease and fewer cases of metastases at diagnosis.
In the United States over the most recent 20 years, Messing said, prostate cancer death rates have been reduced by close to 40%. This occurred without substantial changes in how men were treated (via surgery and radiation therapy). Other models published in the scientific literature have suggested that more than 50% of this reduction is due to early detection.
The technology that allows scientists to profile the entire genome of individual tumors offers new hope for discovering ways to select the best treatment for each patient’s particular type of cancer. However, these profiles produce huge amounts of data, and the volume alone creates unique analytical problems.
In a study published on-line this week in the journal BMC Medical Genomics, researchers from Huntsman
Cancer Institute (HCI) at the University of Utah describe a new analytical approach based on a concept called multiplicity, that can organize large amounts of varied genetic data. The method allows researchers to create three-dimensional models revealing previously unknown relationships among the genes involved with different types of cancer.
“This technique shows similar genetic profiles for different types of cancers, which could open the door to trials of already approved drugs for additional cancers,” said Lewis Frey, Ph.D., assistant professor in the Department of Biomedical Informatics and an HCI investigator. “It can bring to light previously unknown genetic connections between different cancers, helping focus the search for cancer-causing genetic mutations. It makes whole genome data more usable for both clinical and laboratory researchers.”
Stephen R. Piccolo, Ph.D., a postdoctoral research associate in the Department of Biomedical Informatics at the University of Utah, and Mary E. Edgerton, M.D., Ph.D., associate professor in the Department of Pathology at MD Anderson Cancer Center in Houston, Texas, are co-authors of the article. The study was funded in part by an Incentive Seed Grant from the University of Utah, and a National Library of Medicine training grant.
Stick a shovel in the ground and scoop. That’s about how deep scientists need to go in order to find evidence for ancient life on Mars, if there is any to be found, a new study suggests. That’s within reach of Curiosity, the Mars Science Laboratory rover expected to land on the Red Planet next month.
The new findings, which suggest optimal depths and locations to probe for organic molecules like those that compose living organisms as we know them, could help the newest Mars rover scout for evidence of life beneath the surface and within rocks. The results suggest that, should Mars harbor simple organic molecules, NASA’s prospects for discovering them during Curiosity’s explorations are better than previously thought, said Alexander Pavlov of the NASA Goddard Space Flight Center in Greenbelt, Maryland, lead author of the study.
While these simple molecules could provide evidence of ancient Martian life, they could also stem from other sources like meteorites and volcanoes. Complex organic molecules could hint more strongly at the possibility of past life on the planet. These molecules, made up of 10 or more carbon atoms, could resemble known building blocks of life such as the amino acids that make up proteins.
Although complex carbon structures are trickier to find because they’re more vulnerable to cosmic radiation that continuously bombards and penetrates the surface of the Red Planet, the new research by Pavlov and his colleagues provides suggestions for where to start looking. The amounts of radiation that rock and soil is exposed to over time, and how deep that radiation penetrates – an indicator of how deep a rover would have to sample to find intact organic molecules – is a subject of ongoing research.
The scientists report that chances of finding these molecules in the first 2 centimeters (0.8 inches) of Martian soil is close to zero. That top layer, they calculate, will absorb a total of 500 million grays of cosmic radiation over the course of one billion years – capable of destroying all organic material. A mere 50 grays, absorbed immediately or over time, would cause almost certain death to a human.
However, within 5 to 10 centimeters (2 to 4 inches) beneath the surface, the amount of radiation reduces tenfold, to 50 million grays. Although that’s still extreme, the team reports that simple organic molecules, such as a single formaldehyde molecule, could exist at this depth – and in some places, specifically young craters, the complex building blocks of life could remain as well.
The study is scheduled to be published 7 July in Geophysical Research Letters, a journal of the American Geophysical Union.
“Right now the challenge is that past Martian landers haven’t seen any organic material whatsoever,” Pavlov said. “We know that organic molecules have to be there but we can’t find any of them in the soil.”
As Mars revolves around the Sun, it is constantly bombarded by very small meteors and interplanetary dust particles, which have plenty of organic compounds in them, Pavlov said. Therefore, over time they would have accumulated at the Martian surface.
The Mars Science Laboratory is the newest and largest of NASA’s Martian landers and is scheduled to touch down August 2012. Curiosity doesn’t have a shovel but, equipped with drilling technology, it will collect, store, and analyze samples of Martian material down to 5 centimeters below the surface of rock and soil. Past Martian rovers have only collected loose soil atop the surface that has been directly exposed to cosmic radiation, making the possibility for detecting organic molecules exceedingly slim.
When evaluating how deep organic molecules might persist beneath the surface, previous studies have mainly focused on the maximum depth, approximately 1.5 meters (5 feet), that cosmic radiation reaches because beyond that point organic molecules could survive, unharmed, for billions of years, Pavlov said. However, drilling to 1.5 meters or deeper is currently too expensive to engineer for a Martian rover.
So the team focused on more attainable depths – the first 20 cm (8 in) below the surface. They modeled the complex scenario of cosmic ray accumulation and its effects on organic molecules using a collection of important variables, including Martian rock and soil composition, changes in the planet’s atmospheric density over time, and cosmic rays’ various energy levels.
In addition to the finding that some simple carbon-containing molecules could exist within 10 cm (4 in) depth, the scientists emphasize that certain regions on Mars may have radiation levels far lower than 50 million grays near the surface – and so more complex molecules like amino acids could remain intact.
In order to find these molecules within the rover’s drilling range (1 to 5 cm), the scientists found the best bet is to look at “fresh” craters that are no more than 10 million years old, unlike past expeditionary sites that mainly sampled from landscapes undisturbed for billions of years.
Compared to Martian landscapes undisturbed for one billion years or more, relatively young craters exhibit freshly exposed rock and soil that was once deeper beneath the surface. . The new research indicates that this material will have been near the surface for a short enough period of time that it’s overall exposure to harmful radiation would not have been enough to wipe out organic molecules.
“When you have a chance to drill, don’t waste it on perfectly preserved (landscapes),” Pavlov said. “You want to go to fresh craters because there’s probably a better chance to detect complex organic molecules. Let Nature work for you.”
Lewis Dartnell, a postdoctoral researcher at the University College London in the U.K., said the paper was a nice study that combined results from other studies with the latest radiation modeling. Dartnell was not part of the study, but has published previous work involving effects of cosmic radiation on the Martian surface.
“The next logical step,” Dartnell said, “is to actually experiment and have a radiation source hit amino acids with radiation of similar energies as cosmic rays and determine how quickly those amino acids are destroyed because models can only do so much.”
Curiosity is set to land in Gale crater – the same crater where the Spirit rover landed in 2004– on August 6. Whether this 3.5-billion-year-old crater has fresher craters within it is uncertain. However, Pavlov hopes that his team’s findings will at least help guide NASA on where to drill once the rover has landed and influence where future generations of rover landers will touch down.
In the July 6 issue of Cell Stem Cell, researchers at the University of California, San Diego School of Medicine describe how human epidermal progenitor cells and stem cells control transcription factors to avoid premature differentiation, preserving their ability to produce new skin cells throughout life.
The findings provide new insights into the role and importance of exosomes and their targeted gene transcripts, and may help point the way to new drugs or therapies for not just skin diseases, but other disorders in which stem and progenitor cell populations are affected.
Stem cells, of course, are specialized cells capable of endlessly replicating to become any type of cell needed, a process known as differentiation. Progenitor cells are more limited, typically differentiating into a specific type of cell and able to divide only a fixed number of times.
Throughout life, human skin self-renews. Progenitor and stem cells deep in the epidermis constantly produce new skin cells called keratinocytes that gradually rise to the surface where they will be sloughed off. One of the ways that stem and progenitor cells maintain internal health during their lives is through the exosome – a collection of approximately 11 proteins responsible for degrading and recycling different RNA elements, such as messenger RNA that wear out or that contain errors resulting in the translation of dysfunctional proteins which could potentially be deleterious to the cell.
“In short,” said George L. Sen, PhD, assistant professor of medicine and cellular and molecular medicine, “the exosome functions as a surveillance system in cells to regulate the normal turnover of RNAs as well as to destroy RNAs with errors in them.”
Sen and colleagues Devendra S. Mistry, PhD, a postdoctoral research fellow, and staff scientist Yifang Chen, MD, PhD, discovered that in the epidermis the exosome functions to target and destroy mRNAs that encode for transcription factors that induce differentiation. Specifically, they found that the exosome degrades a transcription factor called GRHL3 in epidermal progenitor cells, keeping the latter undifferentiated. Upon receiving differentiation inducing signals, the progenitor cells lose expression of certain subunits of the exosome which leads to higher levels of GRHL3 protein. This increase in GRHL3 levels promotes the differentiation of the progenitor cells.
“Without a functioning exosome in progenitor cells,” said Sen, “the progenitor cells prematurely differentiate due to increased levels of GRHL3 resulting in loss of epidermal tissue over time.”
Sen said the findings could have particular relevance if future research determines that mutations in exosome genes are linked to skin disorders or other diseases. “Recently there was a study showing that recessive mutations in a subunit of the exosome complex can lead to pontocerebellar hypoplasia, a rare neurological disorder characterized by impaired development or atrophy of parts of the brain,” said Sen. “This may potentially be due to loss of progenitor cells. Once mutations in exosome complex genes are identified in either skin diseases or other diseases like pontocerebellar hypoplasia, it may be possible to design drugs targeting these defects.”
Funding for this research came, in part, from the National Institutes of Health grant K01AR057828-04 and a Ray Thomas Edwards Award.
The image shows the orbits of the Martian moons Phobos and Deimos and the spread of potential particle trajectories from an asteroid impact on Mars. (Credit: Purdue University image/courtesy of Loic Chappaz)
A mission to a Martian moon could return with alien life, according to experts at Purdue University, but don’t expect the invasion scenario presented by summer blockbusters like “Men in Black 3” or “Prometheus.”
“We are talking little green microbes, not little green men,” said Jay Melosh, a distinguished professor of earth, atmospheric and planetary sciences and physics and aerospace engineering at Purdue. “A sample from the moon Phobos, which is much easier to reach than the Red Planet itself, would almost surely contain Martian material blasted off from large asteroid impacts. If life on Mars exists or existed within the last 10 million years, a mission to Phobos could yield our first evidence of life beyond Earth.”
Melosh led a team chosen by NASA’s Planetary Protection Office to evaluate if a sample from Phobos could contain enough recent material from Mars to include viable Martian organisms. The study was commissioned to prepare for the failed 2011 Russian Phobos-Grunt mission, but there is continued international interest in a Phobos mission, he said. It will likely be a recurring topic as NASA reformulates its Mars Exploration Program.
A Phobos mission was discussed at NASA’s Concepts and Approaches for Mars Exploration workshop and a report issued Tuesday stated that the Martian moons are “important destinations that may provide much of the value of human surface exploration at reduced cost and risk.”
Melosh collaborated with Kathleen Howell, the Hsu Lo Professor of Aeronautical and Astronautical Engineering, and graduate students Loic Chappaz and Mar Vaquero on the project.
The researchers combined their expertise in impact cratering and orbital mechanics to determine how much material was displaced by particular asteroid impacts and whether individual particles would land on Phobos, the closer of the two Martian moons.
The team concluded that a 200-gram sample scooped from the surface of Phobos could contain, on average, about one-tenth of a milligram of Mars surface material launched in the past 10 million years and 50 billion individual particles from Mars. The same sample could contain as much as 50 milligrams of Mars surface material from the past 3.5 billion years.
“The time frames are important because it is thought that after 10 million years of exposure to the high levels of radiation on Phobos, any biologically active material would be destroyed,” Howell said. “Of course older Martian material would still be rich with information, but there would be much less concern about bringing a viable organism back to Earth and necessary quarantine measures.”
When an asteroid hits the surface of a planet it ejects a cone-shaped spray of surface material, similar to the splash created when someone does a cannonball into a swimming pool. These massive impacts pulverize the surface material and scatter high-speed fragments. The team calculated that the bulk of the fragments from such a blast on Mars would be particles about one-thousandth of a millimeter in diameter, or 100 times smaller than a grain of sand, but similar in size to terrestrial bacteria.
The team followed the possible paths the tiny particles could take as they were hurtled from the planet’s surface through space, examining possible speeds, angles of departure and orbital forces. The team plotted more than 10 million trajectories and evaluated which would intercept Phobos and where they might land on the moon during its eight-hour orbit around Mars.
The probability of a particle landing on Phobos depends primarily on the power of the blast that launched it from the surface, Chappaz said.
“It is estimated that during the past 10 million years there have been at least four large impact events powerful enough to launch material into space, and we focused on several large craters as possible points of origin,” he said. “It turns out that no matter where Phobos is in its orbit, it would have captured material from these powerful impact events.”
After the team submitted its report, scientists identified a large, nearly 60-kilometers-in-diameter crater on Mars. The crater, named Mojave, is estimated to be less than 5 million years old, and its existence suggests that there would be an even greater amount of Martian material on Phobos that could contain viable organisms than estimated, Melosh said.
“It is not outside the realm of possibility that a sample could contain a dormant organism that might wake up when exposed to more favorable conditions on Earth,” he said. “I participated in a study that found that living microbes can survive launch from impacts on rock, and other studies have shown some microscopic organisms can tolerate a lot of cosmic radiation.”
This possibility has been a consideration for some time, and Michael Crichton’s “The Andromeda Strain” brought it to public consciousness in 1969. However the movie scenario of a fatal contamination is unlikely, Melosh said.
“Approximately one ton of Martian material lands on Earth every year, ” he said. “There is a lot more swapping back and forth of material within our solar system than people realize. In fact, we may owe our existence to life on Mars.”
Howell also is optimistic that life is not unique to Earth.
“It’s difficult to believe there hasn’t been life somewhere out there in the vast expanse of space,” Howell said. “The question is if the timeline overlaps with ours enough for us to recognize it. Even if we found no evidence of life in a sample from Phobos, it would not be a definitive answer to the question of whether or not there was life on Mars. There still may have been life that existed too long ago for us to detect it.”
Melosh recently presented the team’s findings at a joint NASA and European Space Agency meeting in Austria, and Chappaz will present the data at a meeting on July 14 in Mysore, India.
Scientists could take greater strides toward crop improvement if there were wider adoption of advanced techniques used to understand the mechanisms that allow plants to adapt to their environments, current and former Purdue University researchers say.
In a perspective for the journal Science, Brian Dilkes, a Purdue assistant professor of genetics, and Ivan Baxter, a research computational biologist for the U.S. Department of Agriculture’s Agricultural Research Service, argue that today’s technology could allow scientists to match physiological and genetic characteristics of plants with the soil characteristics that promote or inhibit their growth. Making those connections could reduce the time necessary to improve plants that are coping with changing environmental and climatic conditions.
“Evolution has solved the problems that we face in terms of adapting plants to grow in a multitude of environments,” Dilkes said. “If we understand these processes, we’ll be able to apply that knowledge to maintaining diversity in natural systems and improving and maintaining crop yield.”
The majority of a plant’s makeup, besides carbon dioxide, comes from elements and minerals absorbed from the soil as the plant grows. The physiological and genetic mechanisms that allow plants to obtain iron from the soil, for instance, can also cause the plant to accumulate other elements. Understanding how those changes interact is an important piece of improving plants, Baxter said.
“This is just a hint of the complexity that’s out there,” said Baxter, a former post-doctoral researcher at Purdue who works for the USDA at the Donald Danforth Plant Science Center in St. Louis. “If we’re going to make the necessary improvements in agricultural productivity, we will have to move forward with these techniques.”
Much of the work done to understand how plants have adapted to their environments focuses on one gene and one element it controls at a time. Pinpointing one or more genes responsible for a particular trait can take years, even decades.
Dilkes and Baxter believe a wider adoption of molecular phenotyping techniques, such as ionomics and genome-wide association mapping, could allow scientists to work with multiple elements and genes at once.
“By focusing on one gene or one element at a time, you miss out on the other physiological mechanisms occurring in the plant,” Dilkes said. “The potential to broaden our understanding of these complex interactions and have a dramatic effect on agriculture is there.”
Genome-wide association mapping allows scientists to find genetic associations among multiple phenotypes, or physical traits. The process quickly shows which genes may be responsible for the physical characteristics.
Ionomics studies the elemental composition of plants and how those compositions change in response to environmental or genetic changes.
“Experiments with thousands of samples are now possible,” Baxter said. “We’ve just started to put these things together.”
Research in Baxter’s lab is supported by the National Science Foundation, the U.S. Department of Energy and the U.S. Department of Agriculture’s Agricultural Research Service.
Compared to normal cells, cancer cells have a prodigious appetite for glucose, the result of a shift in cell metabolism known as aerobic glycolysis or the “Warburg effect.” Researchers focusing on this effect as a possible target for cancer therapies have examined how biochemical signals present in cancer cells regulate the altered metabolic state.
Now, in a unique study, a UCLA research team led by Thomas Graeber, a professor of molecular and medical pharmacology, has investigated the reverse aspect: how the metabolism of glucose affects the biochemical signals present in cancer cells.
In research published June 26 in the journal Molecular Systems Biology, Graeber and his colleagues demonstrate that glucose starvation — that is, depriving cancer cells of glucose —activates a metabolic and signaling amplification loop that leads to cancer cell death as a result of the toxic accumulation of reactive oxygen species, the cell-damaging molecules and ions targeted by antioxidants like vitamin C.
The research, which involved UCLA scientists from the Crump Institute for Molecular Imaging, the Institute for Molecular Medicine, the California NanoSystems Institute, the Jonsson Comprehensive Cancer Center, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and the Department of Pathology and Laboratory Medicine, demonstrates the power of systems biology in uncovering relationships between metabolism and signaling at the network level.
“Most strikingly, our discovery that glucose withdrawal causes both cell death and increased tyrosine phosphorylation is intriguing because increased tyrosine kinase signaling is normally associated with cell growth,” said Nicholas A. Graham, a senior postdoctoral scholar in Graeber’s lab who helped design the project.
To explain the seemingly contradictory result that glucose deprivation reduced viability and at the same time increased signaling, the authors used an unbiased systems-biology approach that included phospho-tyrosine mass spectrometry and other biochemical profiling techniques.
Assessing the “crosstalk” between metabolism and signaling, they discovered that the glucose deprivation activates a positive feedback loop whereby the withdrawal of glucose induces increased levels of reactive oxygen species, which in turn inhibit negative regulators of tyrosine signaling. The resulting supra-physiological levels of tyrosine phosphorylation then generate additional reactive oxygen species.
“Because cancer cells live on the edge of what is metabolically feasible, this amplifying cycle of oxidative stress ultimately overwhelms and kills the cancer cell,” Graeber explained. “These findings illustrate the delicate balance that exists between metabolism and signaling in the maintenance of cancer cell homeostasis.”
In addition, the authors showed the possibility of exploiting this positive feedback loop for therapeutic intervention. Combining short-term glucose deprivation with an inhibitor of tyrosine phosphatases, they demonstrated synergistic cell death in a cancer cell line.
“Understanding the links between metabolism and signaling will empower new therapeutic approaches toward inducing this metabolic catastrophe,” Graham said. “This study provides a framework for rational design of combinatorial therapeutics targeting both metabolism and signaling in cancer.”
The findings by Graeber and his colleagues add to the emerging concept of systems integration between oncogenic signaling networks and the metabolism of malignant tumors. The work lays a foundation for future studies delineating how signaling and metabolism are linked, with the ultimate goal of refining therapeutic strategies targeting cancer metabolism.
The research team also included collaborators from the department of neurology and the human oncology and pathogenesis program at Memorial Sloan–Kettering Cancer Center and the department of pharmacology at Weill–Cornell Medical College.
The research was funded by the National Institutes of Health, UCLA’s Jonsson Comprehensive Cancer Center, and the California Institute of Technology–University of California, Los Angeles, Joint Center for Translational Medicine.
Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.
Duchenne muscular dystrophy, or DMD, is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers.
In a new study, senior author Carmen Bertoni, an assistant professor in the UCLA Department of Neurology, first author Refik Kayali, a postgraduate fellow in Bertoni’s lab, and their colleagues demonstrate the efficacy of a new compound known as RTC13, which suppresses so-called “nonsense” mutations in a mouse model of DMD.
The findings appear in the current online edition of the journal Human Molecular Genetics.
“We are excited about these new findings because they represent a major step toward the development of a drug that could potentially treat this devastating disease in humans,” Bertoni said. “We knew that the compounds were effective in cells isolated from the mouse model for DMD, but we did not know how they would behave when administered in a living organism.”
Nonsense mutations are generally caused by a single change in DNA that disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. Approximately 13 percent of genetic defects known to cause diseases are due to such mutations. In the case of DMD, the “missing” protein is called dystrophin.
For the study, Bertoni and Kayali collaborated with the laboratory of Dr. Richard Gatti, a professor of pathology and laboratory medicine and of human genetics at UCLA. Working with the UCLA Molecular Shared Screening Resource facility at the campus’s California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14.
The Bertoni lab tested RTC13 and RTC14 in a mouse model of DMD carrying a nonsense mutation in the dystrophin gene. While RTC14 was not found to be effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD.
The researchers also compared the level of dystrophin achieved to the levels seen with another experimental compound, PTC124, which has proved disappointing in clinical trials; RTC13 was found to be more effective in promoting dystrophin expression. Just as important, Bertoni noted, the study found that RTC13 was well tolerated in animals, which suggests it may also be safe to use in humans.
The next step in the research is to test whether an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug.
Other study authors included Jin-Mo Ku, Gregory Khitrov, Michael E. Jung and Olga Prikhodko, all from UCLA. The researchers report no conflicts of interest. The work has been supported in large part by the Muscular Dystrophy Association (MDA) and, more recently, by the National Institutes of Health.
UCLA researchers have discovered that a diet enriched with a popular omega-3 fatty acid and an ingredient in curry spice helps to preserve walking ability in rats that have experienced damage to their spinal cords.
The findings, published June 26 in the Journal of Neurosurgery: Spine, suggest that these dietary supplements help repair nerve cells and maintain neurological function after degenerative damage to the neck.
“Normal aging often narrows the spinal canal, putting pressure on the spinal cord and injuring tissue,” said principal investigator Dr. Langston Holly, associate professor of neurosurgery at the David Geffen School of Medicine at UCLA. “While surgery can relieve the pressure and prevent further injury, it can’t repair damage to the cells and nerve fibers. We wanted to explore whether dietary supplementation could help the spinal cord heal itself.”
The UCLA team studied two groups of rats with a condition that simulated cervical myelopathy — a progressive disorder that often occurs in people with spine-weakening conditions like rheumatoid arthritis and osteoporosis. Cervical myelopathy can lead to disabling neurological symptoms, such as difficulty walking, neck and arm pain, hand numbness, and weakness of the limbs. It’s the most common cause of spine-related walking problems in people over 55.
The first group of animals was fed rat chow that replicated a Western diet high in saturated fats and sugar. The second group consumed a standard diet supplemented with docosahexaenoic acid (DHA) and curcumin, a compound in the Indian curry spice turmeric. A third set of rats received a standard rat diet and served as a control group.
Why these supplements? DHA is an omega-3 fatty acid shown to repair damage to cell membranes. Curcumin is a strong antioxidant that previous studies have linked to tissue repair. Both reduce inflammation.
“The brain and spinal cord work together, and years of research demonstrate that supplements like DHA and curcumin can positively influence the brain,” said study co-author Fernando Gomez-Pinilla, a professor of neurosurgery at UCLA. “We suspected that what works in the brain may also work in the spinal cord. When we were unable to find good data to support our hypothesis, we decided to study it ourselves.”
The researchers recorded a baseline of the rats walking and re-examined the animals’ gait on a weekly basis. As early as three weeks, the rats eating the Western diet demonstrated measurable walking problems that worsened as the study progressed. Rats fed a diet enriched with DHA and curcumin walked significantly better than the first group even six weeks after the study’s start.
Next, the scientists examined the rats’ spinal cords to evaluate how diet affected their injury on a molecular level. They measured levels of three markers respectively linked to cell-membrane damage, neural repair and cellular communication.
The rats that ate the Western diet showed higher levels of the marker linked to cell-membrane damage. In contrast, the DHA and curcumin appeared to offset the injury’s effect in the second group, which displayed marker levels that were equivalent to the control group.
Levels of the markers linked to neural repair and cellular communication were significantly lower in the rats raised on the Western diet. Again, levels in the animals fed the supplemented diet appeared similar to those of the control group.
“DHA and curcumin appear to invoke several molecular mechanisms that preserved neurological function in the rats,” said Gomez-Pinilla. “This is an exciting first step toward understanding the role that diet plays in protecting the body from degenerative disease.”
“Our findings suggest that diet can help minimize disease-related changes and repair damage to the spinal cord,” Holly said. “We next want to look at other mechanisms involved in the cascade of events leading up to chronic spinal-cord injury. Our goal is to identify which stages will respond best to medical intervention and identify effective steps for slowing the disease process.”
Other co-authors included Dr. Donald Blaskiewicz, Aiguo Wu, Cameron Feng and Zhe Ying, all of UCLA. Their research was supported by grants from the National Institutes of Health (RO1 NS056413) and the Craig H. Neilsen Foundation.