BreakThrough Digest Medical News |
- Why cancer rate increases with age (it’s not what you think)
- A better way to test new treatments? Approach could help patients and give useful results
- Naked mole rat may hold the secret to long life
- Chronic inflammation in the brain leads the way to Alzheimer’s disease
| Why cancer rate increases with age (it’s not what you think) Posted: 01 Jul 2012 09:00 PM PDT
Cancers are age-related, much more frequent in the old than in the young. A University of Colorado Cancer Center review published today in the journal Oncogene argues against the conventional wisdom that the accumulation of cancer-causing mutations leads to more cancer in older people, instead positing that it is the changing features of tissue in old age that promote higher cancer rates in the elderly.
“If you look at Mick Jagger in 1960 compared to Mick Jagger today, it’s obvious that his tissue landscape has changed,” says James DeGregori, PhD, investigator at the University of Colorado Cancer Center and professor of molecular biology at the University of Colorado School of Medicine. “And it’s this change, not the accumulation of cancer-causing mutations, that drives cancer rates higher as we grow older.” For evidence, DeGregori points first to the fact that by the time we stop growing in our late teens, we’ve already accumulated a large fraction of the mutations we will have in our lifetimes. “There’s a mismatch between the mutation curve and the cancer curve,” DeGregori says, meaning that if cancer were due to reaching a tipping point of, say, five or six mutations, we should see higher cancer rates in 20-year-olds, as this is when mutation rate is highest. Second, DeGregori points out that even healthy tissues are full of oncogenic mutations. “These mutations are many times more common than the cancers associated with them,” DeGregori says. Simply, more mutations doesn’t equal more cancer ? not across the aging population and not even in specific tissues. DeGregori’s final two points come from evolution. As we’ve evolved from one-celled, short-lived life forms into multicellular, long-lived humans, we’ve had to develop complicated machinery to maintain our tissues and avoid disease. “But we’re no better at preventing mutations than our yeast or bacteria cousins,” DeGregori says. “You’d think if avoiding mutations was key to avoiding cancer, we’d be better at it than we are.” And finally, if these oncogenes were the evil super-villains they’ve been made out to be, capable of taking over surrounding tissue, then introducing oncogenes into mice stem cells should help rather than hurt these cells’ survival. “Rather, stem cells harboring the oncogenes tend to get weeded out,” says DeGregori. Instead of gathering mutations until they give us cancer, DeGregori says that as we age, the mechanisms that younger adults use to fight cancer, deteriorate. “It’s like what happened to the dinosaurs 65 million years ago,” DeGregori says. “Dinosaurs were great and they weren’t changing that fast ? they were well adapted to their landscape. Until that darn meteor. Suddenly what was fit was no longer fit. The species didn’t have to change their mutation rate ? it was the new landscape that drove speciation. Similarly, what primarily drives cancer rates higher as we age is the changed landscape.” Our healthy cells are optimized for the conditions of our healthy, younger tissue. Change this balance, as does an oncogenic mutation, and they’re no longer a perfect fit for the surroundings ? healthy cells in young bodies quickly outcompete cells with cancerous mutations. But, “when tissue is old, healthy cells are no longer a perfect fit, and mutations might help a cancer cell adapt in ways a healthy cell can’t,” DeGregori says. Blot out the sun with a meteor’s cloud of dust and mammals will eventually outcompete thunder lizards; age tissue past the expiration date evolution’s set and cancer cells can outcompete their normal but aged peers. Contact: Garth Sundem ### |
| A better way to test new treatments? Approach could help patients and give useful results Posted: 01 Jul 2012 09:00 PM PDT
A new approach to testing medical treatment options could ensure that more patients get the most beneficial treatment for them ? but still yield valuable research results that stand up to scientific scrutiny.
The approach tries to overcome a huge chicken-and-egg problem in medical research: Not enough people volunteer for studies of new treatments partly because researchers can’t promise the studies will help them — but without enough volunteers, researchers can’t study new treatment options. But a new “adaptive” way of designing medical studies could help. In a recent paper in the Journal of the American Medical Association, and in several clinical trials now being planned at the University of Michigan Health System and partner institutions, adaptive design has come to the fore. Experts from U-M and other major medical centers say that the approach makes the most sense in situations where time is of the essence ? such as emergency care ? or where the medical stakes are high and there are few good treatment options ? such as some forms of cancer. They also note there are plenty of situations where adaptive design isn’t feasible or needed. But for patients who are being asked to participate in research studies, an adaptive design could help tip the balance between saying yes and saying no. It could also help patients who enter trials have a clearer understanding of what the stakes are for them personally, not just for the generation of patients who will come after them. “It takes more preparation for the researchers up front, and more sophisticated statistical analysis as the trial is going on, but in the end more study volunteers will be more likely to get the best option for them, and the results will still be scientifically sound,” says William Meurer, M.D., a U-M emergency physician who is lead author of the recent JAMA viewpoint article. The “adaptive” approach to clinical trial design centers around how patients are randomly assigned to one of the two or more groups in a study. In a non-adaptive trial, everyone who volunteers from the first patient to the last gets assigned with what amounts to a coin toss, and the groups end up being of similar size. But in an adaptive trial, the trial’s statistical algorithm constantly monitors the results from the first volunteers, and looks for any sign that one treatment is better than another. It doesn’t tell the patients or the study doctors what they’re seeing, but they do start randomly assigning slightly more patients into the group that’s getting the treatment that is starting to look better. In other words, the trial “learns” along the way. “It’s a way of assigning patients at slightly less than random chance, allowing us to do what might be in the best interest of each patient as the trial goes along,” says Meurer, an assistant professor of emergency medicine and neurology at the U-M Medical School. By the end of the trial, one of the groups of patients will therefore be larger, which means the statistical analysis of the results will be trickier and the results might be a little less definitive. But if the number of patients in the trial is large, and if the difference between treatments is sizable, the results will still have scientific validity, Meurer says. A clinical trial of post-stroke blood sugar treatment is one example of this kind of approach. It’s being coordinated by the Neurological Emergencies Treatment Trial network based at U-M, and conducted at dozens of centers including, in coming months, U-M’s own emergency department and inpatient stroke unit. The study, called SHINE, uses an adaptive method of assigning stroke survivors to a target blood sugar level in the first day after their stroke ? with the goal of finding out how much impact blood sugar control has on how well the patients do overall. The study was designed by researchers at the University of Virginia, Medical College of Georgia, University of Texas Southwestern, and the NETT Statistical and Data Management Center at the Medical University of South Carolina. Other emergency treatment studies now being planned at U-M with collaborators from throughout the country with adaptive design include one for therapeutic hypothermia after cardiac arrest, and hypothermia after spinal cord trauma. In both cases, it’s not yet known what length of time for cooling produces the best outcome for patients, though cooling is being used for both types of patients already. In addition, the team has also developed an adaptive comparative effectiveness trial to evaluate three different medications to stop ongoing seizures in patients who have failed first line treatment. When time is of the essence and patients or their loved ones are being asked to make a decision about being in a clinical trial at the very time when they are in a health crisis, and the difference between treatment options could be large, adaptive design can be most powerful, Meurer says. Pharmaceutical companies and medical device manufacturers have been faster to adopt adaptive design for their trials, but academic centers that conduct huge numbers of non-industry trials have not. But when researchers just want to compare two standard treatments to make sure one isn’t grossly inferior, or when they want to pinpoint the precise impact of a preventive measure (such as aspirin) across a large population (such as heart attack survivors), adaptive designs usually won’t help, he notes. “Adaptive design gives us the potential to get it right and put more people where the bang for the buck is, but still have the change be invisible to the physicians and staff carrying out the trial,” Meurer says. “If a particular option helps patients about 10 percent more than other options, but the adaptive design’s impact on the statistical results means that you can only say the effect is somewhere between 9 percent and 11 percent, the tradeoff is still worth it.” ### In addition to Meurer, the JAMA Viewpoint authors are Roger J. Lewis, M.D., PhD of Harbor-UCLA Medical Center, and Donald Berry, Ph.D., of the University of Texas MD Anderson Cancer Center. NETT is headed by William Barsan, M.D., outgoing chair of the U-M Department of Emergency Medicine. Reference: JAMA. 2012;307(22):2377-2378. doi:10.1001/jama.2012.4174 More information about NETT is available at www.nett.umich.edu. To see which U-M clinical trials are currently seeking volunteers, visit www.umclinicalstudies.org The federal government’s Clinicaltrials.gov website has more information on participating in clinical trials at http://clinicaltrials.gov/ct2/info/understand Contact: Kara Gavin |
| Naked mole rat may hold the secret to long life Posted: 01 Jul 2012 09:00 PM PDT
Compared to the average three year life span of a common rat, the 10 to 30 year life of the naked mole rat, a subterranean rodent native to East Africa, is impressive. And compared to the human body, the body of this rodent shows little decline due to aging, maintaining high activity, bone health, reproductive capacity, and cognitive ability throughout its lifetime. Now a collaborative of researchers in Israel and the United States is working to uncover the secret to the small mammal’s long ? and active ? lifespan.
Dr. Dorothee Huchon of Tel Aviv University’s Department of Zoology, Prof. Rochelle Buffenstein of the University of Texas Health Science Center in San Antonio, and Dr. Yael Edrey of the City College of New York are working together to determine whether the naked mole rat’s unusually high levels of NRG-1, a neuroprotecting protein, is behind the naked mole rat’s three-decade life span. Because rodents have an 85 percent genetic similarity to humans, it may hold the key to a longer and healthier life for us as well. This research has been published in the journal Aging Cell. A family trait?
Genetic analysis comparing the mole rat with several other rodent species revealed that high levels NRG-1 in adults correlated with a longer life span. Of all the species the researchers studied, the naked mole rat had the most plentiful and long-lasting supply of the protein, maintaining a consistent level throughout its lifetime. It is concentrated in the cerebellum, the part of the brain important to motor control. Dr. Huchon, an evolutionary biologist, joined the project to lend her expertise on rodent genetics. She studied seven species of rodents, including guinea pigs, mice, and mole rats, to determine the genetic relationships between them. Her analysis revealed that the correlation between life span and NRG-1 levels was independent of evolutionary lineage ? meaning that it was unique to the naked mole rat, not a common trait of these rodent species. Prof. Buffenstein and Edrey monitored NRG-1 levels in a population of naked mole rats ranging in age from one day to 26 years. They found that throughout their lives, levels of NRG-1, essential for normal brain functioning, were sustained. The protein is a neuroprotector, safeguarding the integrity of neurons, which may explain why naked mole rats are able to live so healthfully for such a long period of time. Shaping future aging research
This discovery is an important first step towards understanding how aging ? and the NRG-1 protein in particular ? functions in these interesting animals, says Dr. Huchon. Future research could reveal how NRG-1 helps to maintain neuron integrity and lead to discoveries about human aging as well. The naked mole rat, a burrowing rodent that lives in colonies much like those of ants, has already proven to be an excellent tool for aging and biomedical research because it is resistant to cancer and maintains protein integrity in the brain despite being exposed to oxidative damage, Dr. Huchon says. ### American Friends of Tel Aviv University (www.aftau.org) supports Israel’s leading, most comprehensive and most sought-after center of higher learning. Independently ranked 94th among the world’s top universities for the impact of its research, TAU’s innovations and discoveries are cited more often by the global scientific community than all but 10 other universities. Internationally recognized for the scope and groundbreaking nature of its research and scholarship, Tel Aviv University consistently produces work with profound implications for the future. Contact: George Hunka |
| Chronic inflammation in the brain leads the way to Alzheimer’s disease Posted: 30 Jun 2012 09:00 PM PDT
Research published today in Biomed Central’s open access journal Journal of Neuroinflammation suggests that chronic inflammation can predispose the brain to develop Alzheimer’s disease.
To date it has been difficult to pin down the role of inflammation in Alzheimer’s disease (AD), especially because trials of NSAIDs appeared to have conflicting results. Although the ADAPT (The Alzheimer`s Disease Anti-inflammatory Prevention Trial) trial was stopped early, recent results suggest that NSAIDs can help people with early stages of AD but that prolonged treatment is necessary to see benefit. Researchers from the University of Zurich, in collaboration with colleagues from the ETH Zurich and University of Bern investigated what impact immune system challenges (similar to having a severe viral infection) would have on the development of AD in mice. Results showed that a single infection before birth (during late gestation) was enough to induce long-term neurological changes and significant memory problems at old age. These mice had a persistent increase in inflammatory cytokines, increased levels of amyloid precursor protein (APP), and altered cellular localization of Tau. If this immune system challenge was repeated during adulthood the effect was strongly exacerbated, resulting in changes similar to those seen for pathological aging. Dr Irene Knuesel who led this research explained, “The AD-like changes within the brain of these mice occurred without an increase in amyloid ? (A?). However, in mice genetically modified to produce the human version of A?, the viral-like challenge drastically increased the amount of A? at precisely the sites of inflammation-induced APP deposits. Based on the similarity between these APP/A? aggregates in mice and those found in human AD, it seems likely that chronic inflammation due to infection could be an early event in the development of AD. ### Notes to Editors
1. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central’s open access policy. Article citation and URL available on request on the day of publication. 2. Journal of Neuroinflammation is an open access, peer-reviewed online journal that focuses on innate immunological responses of the nervous system, involving microglia, astrocytes, cytokines, chemokines, and related molecular processes. 3. BioMed Central is an STM (Science, Technology and Medicine) publisher which has pioneered the open access publishing model. All peer-reviewed research articles published by BioMed Central are made immediately and freely accessible online, and are licensed to allow redistribution and reuse. BioMed Central is part of Springer Science+Business Media, a leading global publisher in the STM sector. Contact: Hilary Glover |
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