Research

ROCHESTER, Minn. — March 22, 2012.  It's a natural laboratory for studying heart disease, lung problems, muscle loss, sleeping disorders and new medical technologies. It's also the highest mountain in the world. Mount Everest's extreme altitude puts climbers under the same conditions experienced by patients suffering from heart disease, obesity or advanced age. To take advantage of that, Mayo Clinic researchers are joining an expedition to Everest with National Geographic, The North Face and Montana State University. The Mayo group will monitor up to nine climbers from base camp for the duration of the climb, which will run from mid-April to mid-May. VIDEO ALERT: Additional audio and video resources, including excerpts from an interview with Dr. Johnson describing the research, are available on the Mayo Clinic News Blog. "We can simulate some conditions in oxygen tents and hyperbaric chambers, but only for short periods," says Bruce Johnson, Ph.D., Mayo Clinic physiologist and leader of the scientific expedition. "We're studying the effects of extreme altitude on healthy, active individuals as well as these extreme athletes because what they experience mimics aspects of heart disease." Dr. Johnson, who has conducted research at the South Pole and other mountain ranges, will be joined by three other Mayo investigators: physician-researcher Doug Summerfield, M.D., and scientists Bryan Taylor, Ph.D., and Amine Issa, Ph.D. Mayo Clinic also will send its own reporter to cover the research expedition. Joel Streed of the Mayo Clinic News Network will blog and shoot video from base camp. The coverage can be followed at www.MayoCliniconEverest.com, and on Twitter at #MayoClinic #onEverest. The expedition and other research initiatives are part of Mayo's work to transform medical care. The data generated by the expedition is expected to provide new insights into aging patients and heart disease, and help Mayo develop high-quality, affordable options for patients who need cardiac monitoring.

ROCHESTER, Minn. — Mayo Clinic researchers have trained mouse immune systems to eradicate skin cancer from within, using a genetic combination of human DNA from melanoma cells and a cousin of the rabies virus. The strategy, called cancer immunotherapy, uses a genetically engineered version of the vesicular stomatitis virus to deliver a broad spectrum of genes derived from melanoma cancer cells directly into tumors. In early studies, 60 percent of tumor-burdened mice were cured in fewer than three months and with minimal side effects. Results of the latest study appear this week in the journal Nature Biotechnology. "We believe that this new technique will help us to identify a whole new set of genes that encode antigens that are important in stimulating the immune system to reject cancer. In particular, we have seen that several proteins need to be expressed together to generate the most effective rejection of the tumors in mice," says Richard Vile, Ph.D., a Mayo Clinic researcher in the Department of Molecular Medicine and a coauthor of the study, along with Jose Pulido, M.D., a Mayo Clinic ophthalmologist and ocular oncologist. Dr. Vile's success with melanoma adds to Mayo Clinic's growing portfolio of experimental cancer vaccines, which includes an active clinical trial of vesicular stomatitis vaccines for liver cancers. Future studies could include similar vaccines for more aggressive cancers, such as lung, brain and pancreatic. "I do believe we can create vaccines that will knock them off one by one," Dr. Vile says. "By vaccinating against multiple proteins at once, we hope that we will be able to treat both the primary tumor and also protect against recurrence." The immune system functions on a seek-and-destroy platform and has fine-tuned its capacity to identify viral invaders such as vesicular stomatitis virus. Part of the appeal of building cancer vaccines from the whole spectrum of tumor DNA is that tumors can adapt to the repeated attacks of a healthy immune system and display fewer antigens (or signposts) that the immune system can identify. Cancers can learn to hide from a normal immune system, but appear unable to escape an immune system trained by the vesicular stomatitis virus with the wide range of DNA used in the library approach. "Nobody knows how many antigens the immune system can really see on tumor cells," says Dr. Vile. "By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system. The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated." Much immunotherapy research has slowed because of researchers' inability to isolate a sufficiently diverse collection of antigens in tumor cells. Tumors in these scenarios are able to mutate and reestablish themselves in spite of the body's immune system.

MINNEAPOLIS — Researchers from the University of Minnesota (U of M) in Minneapolis and Mayo Clinic in Rochester, Minn., have been awarded $1.35 million by ...

JACKSONVILLE, Fla. — Researchers have identified a gene that causes adult-onset primary cervical dystonia, an often-painful condition in which patients' necks twist involuntarily. The discovery by a team from the Jacksonville, Fla., campus of Mayo Clinic and the University of Tennessee Health Sciences Center sheds light on a movement disorder that physicians previously could seldom explain. Their research appears in the Annals of Neurology. In 1990, a man with a crooked neck came to see Ryan Uitti, M.D., a neurologist then at Mayo Clinic in Rochester, Minn. Dr. Uitti knew about adult-onset primary cervical dystonia, which results in involuntary twisting of the neck to the left or right, backward or forward. Most people who have it suffer from muscle pain and abnormalities in head position. Some don't think it is all that unusual and may not seek medical help, Dr. Uitti says. "They think they slept wrong at some point, or, because the twisting might straighten out with another maneuver, such as walking backwards, they might actually be accused of being a little crazy," Dr. Uitti says. Dr. Uitti had been taught that there is usually no explanation for the disorder, when it shows up in adulthood. But working with a team of neurologists who have found the genetic causes of other rare conditions, Dr. Uitti began to investigate.

ROCHESTER, Minn. — Mayo Clinic researchers have gained insights into the function of a member of a family of specialized proteins called histone chaperones. Using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, they have determined the 3-D structure and interactions of the histone chaperone Rtt106 down to the atomic details. The findings are published in the journal Nature. "The interactions we described are important for gene silencing and the DNA damage response," says senior author Georges Mer, Ph.D., a Mayo Clinic structural biologist. "This is exciting because our newfound knowledge will help us better understand these fundamental cellular processes." In cells, our DNA is part of a structure called chromatin, comprised of proteins, the majority called histones, which are wrapped with the DNA. Associated with the histones is another group of proteins called histone chaperones, which promote the proper assembly or disassembly of the chromatin during the times our DNA is replicated or repaired when damaged. Their dysfunction has been linked to cancer, aging and other diseases. The Discovery Before this Mayo study, scientists knew that the histone chaperone Rtt106 helped in the deposition of histones — specifically, a complex of histones H3 and H4 — onto the replicating DNA. They did not understand how Rtt106 does this, given that it does not possess any of the known requirements. Histone H3 is in a modified form where one of its amino acids, lysine 56, is acetylated. Rtt106 does not seem to have an acetylated lysine reader domain.

JACKSONVILLE, Fla. — Vitamin D is primarily produced in the body through direct exposure of the skin to sunlight. While it has long been touted for its important role in maintaining healthy bones, more recent research suggests that sustaining healthy levels of vitamin D in the bloodstream can also reduce the risk of common diseases such as heart disease, diabetes and some types of cancer, says a Mayo Clinic researcher. "Unfortunately, many Americans are unaware of these additional health benefits of vitamin D, and some reports suggest that up to one-quarter of the U.S. population have suboptimal levels of vitamin D in their blood — a condition known as hypovitaminosis D," says Alexander Parker, Ph.D., associate professor of epidemiology and urology at Mayo Clinic, Florida, and chair of the Division of Health Sciences Research. One segment of the U.S. population that is at particular risk of having lower than optimal vitamin D levels is the black community, he says. This is primarily because darker skin, with more melanin, reduces the ability to absorb the sunlight necessary to make vitamin D, Dr. Parker says. "Indeed, data from large, national studies have reported that as high as 40 percent of black Americans in the U.S. do not have healthy levels of vitamin D in their blood," he says. "That's important because low vitamin D levels in black Americans have been offered as a potential explanation for some of the racial and ethnic disparities in heart disease, cancers, and other conditions." To begin to address this issue, Mayo Clinic will offer a series of informational presentations followed by question-and-answer sessions regarding the health benefits of vitamin D for black residents. "We believe it is important to pass this information to members of our Jacksonville community, and one way we can effectively do this is to go out into the community, talk to people face to face and be there to answer any questions they may have," Dr. Parker says.

ROCHESTER, Minn. — Mitochondria — subunits inside cells that produce energy — have long been thought to play a role in Alzheimer's disease. Now Mayo Clinic researchers using genetic mouse models have discovered that mitochondria in the brain are dysfunctional early in the disease. The findings appear in the journal PLoS ONE. The group looked at mitochondria in three mouse models, each using a different gene shown to cause familial, or early-onset, Alzheimer's disease. The specific mitochondria changes corresponded with the mutation type and included altered mitochondrial movement, structure, and energy dynamics. The changes happened in the brain even before the mice showed any symptoms such as memory loss. The group also found that the mitochondrial changes contributed to the later loss of mitochondrial function and the onset and progression of Alzheimer's disease. "One of the most significant findings of this study is our discovery of the impact of mitochondrial dysfunction in Alzheimer's disease," says Eugenia Trushina, Ph.D., Mayo Clinic pharmacologist and senior investigator on the study. "We are asking: Can we connect the degree of mitochondrial dysfunction with the progression of symptoms in Alzheimer's disease?" Enlisting the expertise of Mayo researcher Petras Dzeja, Ph.D., the team applied a relatively new method called metabolomics, which measures the chemical fingerprints of metabolic pathways in the cell — sugars, lipids, nucleotides, amino acids and fatty acids, for example. It assesses what is happening in the body at a given time and at a fine level of detail, giving scientists insight into the cellular processes that underlie a disease. In this case, the metabolomic profiles showed changes in metabolites related to mitochondrial function and energy metabolism, further confirming that altered mitochondrial energetics is at the root of the disease process.

MINNEAPOLIS — Researchers from the University of Minnesota in Minneapolis and Mayo Clinic in Rochester, Minn., are another step closer to developing a drug to combat fungal infections — one of the major problems confronting patients with compromised immune systems. The Minnesota Partnership for Biotechnology and Medical Genomics has awarded Mayo biochemist Zhiguo Zhang, Ph.D., and University medicinal chemist Michael Walters, Ph.D., a commercialization grant of $621,934 for the first year of a two-year period. The research team will use the grant for additional studies that will move their drug discovery toward the marketplace. The Need Finding new drugs to fight fungal infections is critical as the numbers of immuno-compromised patients rise due to HIV, organ transplants, and cancer chemotherapy treatments. In certain fungal infections, the mortality rate exceeds 50 percent and in some cases may be as high as 90 percent. Current drugs are becoming compromised as fungi become resistant to them.

ROCHESTER, Minn. — Mayo Clinic nephrologist and researcher Rajiv Kumar, M.D., has been selected to receive the highest professional recognition from the American College of Physicians, the John Phillips Memorial Award, one of the most prestigious honors in internal medicine. Dr. Kumar is internationally recognized for his research accomplishments in nephrology, mineral metabolism and endocrinology, specifically bone disease in the context of kidney failure and the regulation of phosphate and vitamin D metabolism. "Dr. Kumar helped train a generation of nephrologists and served as chair of nephrology with distinction," says Morie Gertz, M.D., chair of internal medicine at Mayo Clinic in Rochester. "His contributions to the understanding of vitamin D and its effects on bone are important enough to impact daily on the lives of patients."

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