UGA researchers develop non-invasive early diagnostic test for gastric cancer

Early detection of cancer may eventually become as easy as taking a home pregnancy test, according to new University of Georgia research.

Two studies recently published in the journal PloS ONE identified for the first time that certain proteins excreted in urine can indicate the presence of gastric cancer.

The researchers initially studied stomach cancer because it is the number two cancer killer in the world.
They hope that with further study, the detection of abnormally abundant proteins in urine will lead to diagnosis of many types of cancer and other diseases, said Ying Xu, lead author of the study and Regents-Georgia Research Allianceeminent scholar of bioinformatics and computational biologyin the UGA Franklin College of Arts and Sciences.

“In theory, the methodology that we developed should be applicable to other cancers,” said Xu, who also is a professor of biochemistry and molecular biology and director of the UGA Institute of Bioinformatics.

Xu and his colleagues, Celine Hong, Juan Cui and David Puett of the Institute of Bioinformatics, identified a protein called endothelial lipase that differed significantly in its abundance in urine samples of stomach cancer patients versus healthy people. Xu said the computational capability presented in the study for predicting which of the abnormally abundant proteins in diseased tissues can be excreted into urine is a key breakthrough in cancer detection. Using samples from already known excretory and non-excretory proteins, the study found that the classification system was more than 80 percent accurate.

Of the 21 urine samples of healthy people, only two did not have the protein. In the 21 urine samples of stomach cancer patients, only one sample was considered to have a relatively high level of the protein; levels in the rest were low or absent. “We are suggesting from this relatively small urine sample set that healthy people should have this protein in their urine,” Xu said.

The researchers are currently working on a larger urine sample set of 200 gastric cancer patients and 200 healthy people. “If the EL protein still has the 10 to 15 percent miscalculation rate as with the 21 versus 21 samples, I think we have found a good diagnostic marker for stomach cancer and potentially other cancers,” said Xu.

Now that the researchers have identified a protein marker, Xu says they should be able to develop a method where urine can change the color of a piece of paper to indicate the presence or absence of the protein, similar to the way a home pregnancy test works. The researchers hope to find multiple protein markers for each cancer to increase the accuracy of the test.

Although the test is not yet 100 percent accurate, it can lead at-risk patients to seek a more comprehensive exam, said Xu. Current procedures such as endoscopy are invasive, uncomfortable and may be avoided by many people. “A person could go get a urine test, and if the marker protein is present, then they are generally stomach-cancer free,” said Xu. “If the protein is not present, we might suggest that they get their stomach checked.”

The researchers began by studying a set of 1,500 proteins known to be excreted in urine and identified a list of features that distinguish them from proteins that are not excreted into urine. Identifying these distinguishing features allowed them to develop a classification system that could predict which proteins in cancerous tissues are excreted into urine.

Xu and his colleagues then used microarrays—chips that are about the size of a stamp that contain nearly twenty thousand human genes—to identify which proteins varied in abundance in the cancerous versus non-cancerous tissues. Messenger RNA (mRNA) molecules extracted from the sample tissues are converted to complementary DNAs (cDNAs) and hybridize with their complement genes on the microarray and light up as spots when the corresponding mRNAs are abundant. The researchers then identified proteins corresponding to those genes that appeared at significantly different levels in the cancer and non-cancer samples. From there, the researchers were able to determine which of the abnormally abundant proteins were secreted into the blood and then excreted in urine using the classification method they developed.

The UGA researchers work in conjunction with a team of researchers led by Fan Li of Jilin University in China, where Xu spends two months a year working with medical doctors and researchers on sample collection and carrying out microarray experiments. This long-term collaboration has led to the establishment of the Jilin University/University of Georgia Joint Research Center for Systems Biology. The researchers are currently collecting tissues from patients with different types of cancer to identify more protein markers that can be detected in urine.

The study was supported by the UGA President’s Venture Fund, the Office of Vice President for Research, the Georgia Cancer Coalition, the Georgia Research Alliance, Jilin University and the National Institutes of Health.

To learn more about the UGA Institute of Bioinformatics, see http://www.bioinformatics.uga.edu/. To learn more about the Franklin College of Arts and Sciences department of biochemistry and molecular biology, see http://www.bmb.uga.edu/.

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UGA compound offers new hope for treatment of painful adult shingles

Researchers at the University of Georgia and Yale University have discovered a compound with the potential to be more effective than existing agents in treating the very painful blisters known as shingles—a condition that affects up to 30 percent of Americans, mostly elderly, and for which no specific treatment exists.

Most adults remember the fever, itchy blisters and possibly tiny scars they experienced as children when they had chickenpox, which is caused by the varicella-zoster virus, or VZV.Unfortunately, that memory can come back—with a vengeance—when they are older. The VZV virus from childhood chickenpox hides in the nerves, emerging most frequently in adults over the age of 60 as a blistering rash on one side of the body. The rate of complications, including nerve pain that can persist for months or years after the shingles attack is gone, also increases with age.

The novel and effective anti-shingles agent called L-BHDA may change that. Rights to the shingles treatment have been licensed to Bukwang Pharmaceutical Company for preclinical investigations by the University of Georgia Research Foundation, Inc. and Yale University.

“We need new options for medications with increased potency and specificity that can treat VZV, including strains that may be resistant to existing drugs,” said medicinal chemist Chung (David) Chu, Distinguished Research Professor of Pharmaceutical and Biomedical Sciences at UGA, one of the inventors of L-BHDA.

A collaboration between Chu and co-inventor Yung-Chi (Tommy) Cheng, the Henry Bronson Professor of Pharmacology at Yale, has resulted in an extensive portfolio of antiviral compounds that target such diseases as HIV, shingles, hepatitis and cancers.

Chu, who is head of the Drug Discovery Group in the UGA College of Pharmacy, said that although there are generic antiviral drugs to reduce the duration and pain of shingles, and a variety of pain medications and topical creams to relieve long-term pain, “They are only moderately effective.We need more effective anti-VZV agents.

“L-BHDA has the potential to be more effective than existing agents,” said Chu. He noted that the new compound has been tested in the laboratory and demonstrated in mice models by a group of researchers headed by Jennifer Moffat, associate professor of microbiology and immunology, State University of New York Upstate Medical University.

A vaccine to prevent shingles, available to older adults since 2006, can cut the likelihood of a shingles attack in half. However, according to a recent study in the American Journal of Preventive Medicine, only a small percentage of older people receive the shot, principally because of cost, lack of insurance reimbursement and shortage of supply.

It is likely that immunization against chickenpox during childhood also protects against shingles, because the vaccine uses a weakened strain of the virus. However, the vaccine was only introduced in 1995, and there are not enough data to provide a definitive answer.

“Dr. Chu and Dr. Cheng have been working diligently to fill a much needed gap in the treatment options for such a prevalent disease,” said Rachael Widener, UGARF technology licensing manager. “Before the chicken pox vaccine became widely used in the mid-1990s, older, unvaccinated individuals would have their immunity boosted naturally.

“Now, with less exposure to chicken pox, shingles is becoming more prevalent,” said Widener. “This, combined with the aging baby boomer population, underscores the need for more directed treatment. We are hopeful that L-BHDA will allow patients to get well sooner and feel less pain, and will lessen their chances of complications.”

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UGA researchers develop rapid diagnostic test for common type of pneumonia

University of Georgia researchers have developed a technique that can diagnose a common type of pneumonia within minutes, potentially replacing existing tests that can take several days for results.
The researchers, whose findings are detailed online in the journal PLoS ONE, detected Mycoplasma pneumoniae, which causes atypical or “walking pneumonia,” in true clinical samples with over 97 percent accuracy using a recently-developed nanotechnology-based platform.

“If you can make a positive identification from a 10-minute test, then appropriate antibiotics can be prescribed, limiting both the consequences in that patient and the likelihood that it will spread to others,” said lead-author Duncan Krause, a professor in the department of microbiology in the UGA Franklin College of Arts and Sciences.

Krause and his colleagues built upon an existing technology called surface-enhanced Raman spectroscopy, which works by detecting spectral signatures of a near-infrared laser as it scatters off a biological specimen. They were able to enhance the Raman signal by using silver nanorod arrays to detect the tiny bacteria in throat swab specimens.

Krause, who also directs the interdisciplinary UGA Faculty of Infectious Diseases, compared the nanorod array developed by collaborator Yiping Zhao, director of the UGA Nanoscale Science and Engineering Center, to a brush with densely packed bristles, where each of the tiny silver rods extends out at a specific angle. The sample, such as bacteria from a throat swab, penetrates among the bristles, where the spectral signature produced by the laser is amplified and then analyzed by a computer program.

Krause noted that infections due to M. pneumoniae are very common yet difficult to diagnose. The bacterium is a major cause of respiratory disease in humans and the leading cause of pneumonia in older children and young adults.

“Walking pneumonia feels like a bad chest cold that will not go away,” he explained. “It can persist for weeks and even months and can cause permanent damage to the lungs if not diagnosed promptly. A delay in diagnosis extends the likelihood for complications as well as continued transmission of the infection to others.”

Krause said the device can be reduced to a size that could fit in a briefcase, although their testing is currently done only in a laboratory setting. “Our hope is that when we begin to explore the capabilities of this technology, it can be applied in point-of-care testing,” he added. “Then the impact becomes truly significant.”

Krause hopes the combined efforts of the research specialists in nanotechnology and infectious disease will eventually be able to determine if the technique is effective in detecting other pathogens in clinical samples. “We need to do a thorough job with mycoplasmas first,” said Krause. “Then we can go to other clinical samples and ask the same questions with other infectious agents.”

Funding for the research was provided by the U.S. Army Research Laboratory, the National Science Foundation and the Georgia Research Alliance.

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UGA researchers identify key enzyme that regulates the early growth of breast cancer cells

New University of Georgia research, published this week in the early online edition of the journal Proceedings of the National Academy of Sciences, has found that blocking the action of an enzyme called GnT-V significantly delays the onset and spread of tumors in mice with cancer very similar to many cases of human breast cancer.

When the GnT-V enzyme activity in the cells was increased in mammary gland cells, they increased proliferation and began to take on many characteristics of cancer cells. Using a mouse model of human breast cancer, tumors appeared when the enzyme was deleted, but onset was delayed an average of 10 weeks in the mice.

“In human terms,” said Michael Pierce, director of the UGA Cancer Center and study co-author, “the corresponding delay would be many months and maybe years. You basically are slowing everything down and keeping the cancer from forming and progressing very early.” Slowing the pace of the cancer could eliminate its spread to other organs, keeping it localized where it could be treated successfully, Pierce explained.

The researchers, lead by Hua-Bei Guo, assistant research scientist in the department of biochemistry and molecular biology in the Franklin College of Arts and Sciences, stimulated breast cancer formation in mouse mammary glands by over-expressing a her-2 protein that is a growth receptor on the cell surface. The researchers note that over-expression of her-2 is associated with 25 to 30 percent of human breast cancers.

The GnT-V enzyme makes glycans, which are sugars on the cell surface that change in defined ways when the cell becomes cancerous. Glycans are released from the cell as glycoproteins, making them a promising early-detection marker in blood. The researchers studied a glycan made by GnT-V that appears when normal breast cells become cancerous. The GnT-V glycan product is found on her-2 and other receptors and acts to regulate the number of cancer stem cells in the tissue. The number of these cancer stem cells determines how rapidly the cancer will form and develop.

“Glycans often are ignored by scientists, because they’re very complicated and present unusual problems to identify and understand,” said Pierce. “This study is an example of how particular glycans that are present on various cell receptors can actually modulate the onset of tumor formation. That may give us new drug targets and new ways to kill the cancer cells specifically.”

The finding of Guo and the research team at UGA’s Complex Carbohydrate Research Center that the elimination of a glycan-synthesizing enzyme significantly reduced the population of breast cancer stem cells is unprecedented, they note.

“That population of cells appears to drive breast tumor formation in many cases,” said Pierce, who also is UGA’s Mudter Professor in Cancer Research, “and our research suggests that glycans may be potential targets to kill them selectively.”

Pierce likened the cancerous stem cells to the queen of an ant colony. “You can try to get rid of the anthill, but it will just come back if you don’t kill the queen,” Pierce said. “If we can target those cancer stem cells for elimination, that would be the most effective treatment.”

The research was supported by the National Institutes of Health. For more information on the UGA Cancer Center, see www.uga.edu/cancercenter/.

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UGA discovery holds promise for treatment of diabetes and other debilitating diseases

Two University of Georgia animal science researchers introduced to the world 13 pigs that may hold the key to new therapies to treat human diseases, including diabetes. Announced this week, the discovery marks the first time pluripotent stem cells, or cells that can turn into any type of cell in the body, have been created from adult livestock.

We now for the first time have a method to make pigs that can be a source of cells and organs for regenerative medicine in a meaningful way said Steven L. Stice, a Georgia Research Alliance Eminent Scholar in Reproductive Physiology. A faculty member in the UGA College of Agricultural and Environmental Sciences, Stice also directs UGA's Regenerative Bioscience Center. The technique called induced pluripotent stem cells had only previously been shown to make live offspring in mice.

"These first-in-the-world, pig-induced pluripotent cells-generated animals can eventually be used to provide and search for better therapies and cures for human disease and regenerative conditions," Stice said.

The discovery is a new tool for researchers who need to determine which sources of cells, adult or earlier stages such as embryonic or induced pluripotent stem cells, will work best for each disease.

The induced pluripotent stem cells piglets were born Sept. 3, 2009. The process used avoids the more problematic and controversial cloning process while making it easier to make the genetic changes necessary to develop pigs as a better source of cells and organs for transplantation.

"Although induced pluripotent stem cell technology was first successful in mice, they aren't always a good model to study human disease and they are not a good source of tissue and organs for therapy,"  Stice said. "Pigs are often the best way to go."

Stice credits Franklin West, an assistant research scientist, with perfecting the method.

"I've worked on this for about 20 years," Stice said. "Franklin found the way to make it work."

The pluripotent stem cells incorporated naturally into the developing fetuses and contributed to the development of many cell types of the body, such as lungs, kidney, heart, skin or muscle, producing healthy piglets, West said. And 80 percent of the animals produced using this new method are a product of these stem cells, a very high percentage.

The new process will be valuable for a research project under way in partnership with Emory University to find better therapies for diabetes.

"Islets that produce insulin and other hormones related to regulating blood sugar are found in the pancreas," Stice said. "It is well known that porcine islet cells could be a major break through in the treatment of Type I (juvenile) diabetes if they were not rejected by the human immune system. This new method will allow researchers to make the necessary genetic changes to dampen or potentially eliminate the rejection of the new stem cells and then we can make animals from these stem cells."

Another goal, Stice said, is for the study results to lead the way to healthier, more environmentally friendly and disease-resistant livestock, and ones that could help reduce poverty or starvation in developing countries.

Once the new pigs reach sexual maturity and Stice and West determine if the pigs produce viable sperm and egg cells, they can begin naturally mating. The offspring of the current pigs will produce the cells needed to move into the therapy stage and clinical trials.

Details of the discovery will be published in the journal Stem Cells and Development next month.

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UGA Study finds significantly worse outcomes in cancer patients with cognitive impairment

A new study published by researchers from the University of Georgia and the Moffitt Cancer Center in Tampa, Fla., has found that cancer patients with dementia have a dramatically lower survival rate than patients with cancer alone, even after controlling for factors such as age, tumor type and tumor stage.

But the study, published in the early online edition of the journal Critical Reviews in Oncology/Hematology, also argues that a diagnosis of dementia shouldn’t discourage the use of cancer screenings and appropriate cancer treatments.

“As the population ages and as treatments improve, we’re going to see more patients with both dementia and cancer,” said lead author Claire Robb, assistant professor in the UGA College of Public Health. “And right now there are no guidelines for oncologists as to how to treat these patients.”

Robb and her co-authors in the Senior Adult Oncology Program at Moffitt compared the outcomes of 86 cancer patients with cognitive impairment to a control group of 172 patients with cancer alone. They found that cancer patients with dementia survived an average of four fewer years.

Robb, who is also a researcher in the UGA Cancer Center, said that the reason for the disparity is unclear. She notes that the patients in both groups received similar treatment and that the survival gap persists even after controlling for age, tumor type and tumor stage.

But Robb pointed out that within the cognitively impaired group, there was a dramatic difference in survival time between those with mild cognitive impairment and those with moderate to severe impairment. People with mild cognitive impairment often have problems with thinking and memory yet can still live independently; those with moderate to severe dementia forget details about current events, lose awareness and have difficulty with basic tasks such as preparing meals or choosing proper clothing. The researchers found that while patients with moderate to severe dementia had an average survival time of eight months, those with mild dementia had an average survival time of nearly four and a half years.

“Some people would argue against treating patients with mild cognitive impairment because they’re going to have a shorter survival,” Robb said. “But, you know, 53 months—almost 4 and a half years—is a pretty significant amount of time to live.”

The patients in the UGA/Moffitt study generally received the same treatment regardless of cognitive status, but other studies have found that patients with dementia often receive fewer cancer screenings and undergo less aggressive treatment. One study found that physicians were significantly less likely to recommend a mammogram for a woman with dementia than without, while another found that patients with dementia were twice as likely to have colon cancer reported only after death. Another study of breast cancer patients found that those with dementia were 52 percent less likely to have the tumor removed surgically, 41 percent less likely to undergo radiation therapy, 39 percent less likely to undergo chemotherapy and nearly three times more likely to receive no treatment.

“The fact that cognitively impaired patients seen in our Senior Adult Oncology Program received treatments similar to unimpaired patients while epidemiologic data show a marked difference in treatment provides food for thought,” said study co-author Dr. Martine Extermann, associate faculty member at Moffitt. “Although this might reflect a referral bias in which those who volunteered to participate in the study are different from the general population, it might also indicate that such patients benefit from a specialized evaluation and management in a geriatric oncology program.”

Robb emphasized that she does not advocate overly aggressive treatment for patients who are in the late stages of dementia, but urges the creation of guidelines to help ensure that cognitively impaired cancer patients receive appropriate treatment.

“People have thought about the impact of the aging population on rates of cancer and dementia, but not much attention has been paid to what happens when the diseases coincide,” Robb said. “We’re going to be seeing more cases like these, and, if anything, I hope our research raises awareness of this situation.”

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Emory/UGA Flu Center Is One of Six Centers Leading National H1N1 Research Response

In a multi-pronged attack against the H1N1 virus, researchers at Emory University are using a new method of rapidly producing highly targeted monoclonal antibodies to develop a diagnostic test as well as a temporary therapy to stave off the H1N1 (swine flu) virus. The antibodies, which can be isolated from a small amount of the blood of humans infected with the virus, could be targeted against H1N1 and rapidly reproduced to detect or attack the virus. The monoclonal antibody technology was described last April in the journal Nature and is being developed in collaboration with scientists at the University of Chicago.

In addition, Emory scientists, along with colleagues at the Centers for Disease Control and Prevention (CDC), are using virus-like particles (VLPs) to develop a quicker, more efficient alternative to the current method of making flu vaccine by growing it in chicken eggs. VLPs are empty shells that look like viruses but don’t reproduce. In March, the scientists described the effectiveness of their VLP vaccine in mice in the journal PLoS (Public Library of Science) One.

An Emory-University of Georgia Influenza Pathogenesis and Immunology Research Center (IPIRC) is a key component in a national scientific effort to address the H1N1 (swine flu) outbreak. The intensive U.S. research initiative, led by the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC), is centered in six national NIH Centers of Excellence for Influenza Research and Surveillance, including the one led by Emory University and UGA.

“Emory has one of the world’s leading groups of infectious disease experts, vaccine scientists, immunologists and microbiologists,” says David S. Stephens, MD, vice president for research in Emory’s Woodruff Health Sciences Center. “Our research and groundbreaking discoveries by scientists at the Emory Vaccine Center, the Yerkes National Primate Research Center, Emory University School of Medicine and collaborators at the University of Georgia provide a strong basis for our contribution to this coordinated national effort against H1N1.”

Emory scientists in the flu research center are conducting several key projects as part of the national research effort. These include determining how the H1N1 virus enters cells, is transmitted, and how that process might be interrupted; finding out whether prior exposure to other influenza viruses may help or hinder immune responses to the new virus; assessing possible pre-existing immunity to H1N1 in different age groups; analyzing the recovery of infected patients; developing a method to quickly make monoclonal antibodies targeted to the H1N1 virus; and beginning the initial stages of a new vaccine.

At the University of Georgia, scientists are studying how the H1N1 virus is transmitted between animals; finding out how the virus infects human airway cells; developing diagnostic tests to distinguish different virus strains; evaluating the stability of the virus; and testing vaccines and anti-viral drugs against the virus.

“Our scientific team is proud to be contributing to the public good as one of the six influenza research centers in the U.S.,” says Richard Compans, PhD, director of the Emory-UGA center. “The pairing of Emory's expertise with strengths at UGA in animal pathology creates a uniquely effective combination for studying crossover viruses such as 'swine flu.’ We expect to make significant contributions to this national research effort.”

The Emory-UGA IPIRC, along with the five other national flu centers, was established in April 2007 with a seven-year, $32.8 million contract from the NIH.

In the event of a public health emergency involving the emergence and spread of an influenza pandemic in humans, the network of centers is directed to “be on the frontline” to implement the NIAID Pandemic Public Health Research Response Plan.

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UGA to Host Stem Cell Therapies for Spinal Cord Injuries Workshop April 4

Following President Barack Obama's decision to lift the ban on federal funding for embryonic stem cell research, medical and scientific experts will converge at the University of Georgia to discuss how recent advances in stem cell research can be turned into cures for spinal cord injuries.

The second Spinal Cord Workshop, a program of the Bedford Stem Cell Research Foundation, will be held on Saturday, April 4 from 8:30 a.m. to 5:30 p.m. at the Paul D. Coverdell Center for Biomedical and Health Sciences in Athens, Ga.

Every year close to 11,000 people sustain spinal cord injuries in the United States, while more than 200,000 Americans live each day with a disability caused by them.

“Because spinal cord injury usually occurs in otherwise healthy, young adults, it is an especially attractive candidate for a cure for stem cell therapy,” said Ann Kiessling, director of the Bedford Stem Cell Research Foundation. “The big question is whether a ‘moon shot’ approach will produce a cure, or if there is still too much basic science yet unknown.”

The workshop is hosted by UGA’s Regenerative Bioscience Center. Additional support is provided by the UGA Biomedical and Health Sciences Institute, the Shepherd Center in Atlanta and Millipore, Inc.

“The University of Georgia is fortunate to team up with the Bedford Foundation to host these leading experts in spinal cord therapies to discuss and develop new paths forward for spinal cord injuries,” said Steven Stice, director of the Regenerative Bioscience Center and a UGA College of Agricultural and Environmental Sciences professor. “In addition, Georgia’s recent legislation aimed at restricting stem cell research makes this workshop an especially timely one.”

Created in 1996, the Bedford Stem Cell Research Foundation is a Massachusetts-based public charity and biomedical institute conducts stem cell and related research for diseases and conditions that currently have no cure.

The Regenerative Bioscience Center brings UGA’s expertise, resources and accomplishments in human embryonic stem cell research under one umbrella, while contributing to the university’s educational and outreach missions with student research experiences and public lectures, symposia and workshops.

The event serves as a follow-up to the inaugural Spinal Cord Workshop held at UGA in March 2008. For more information, go to the Web site www.spinalcordworkshop.org.

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Study Suggests Blood Test for Alzheimer’s Possible

Researchers have revealed a direct relationship between two specific antibodies and the severity of Alzheimer’s disease symptoms, raising hopes that a diagnostic blood test for the devastating disorder is within reach.

Researchers from the University of Georgia, the Charlie Norwood VA Medical Center in Augusta and the Medical College of Georgia compared antibody levels in blood samples from 118 older adults with the participant’s level of dementia. The team, whose results appear in the current edition of Journal of Gerontology: Medical Sciences, found that the concentration of two specific proteins that are involved in the immune response increases as the severity of dementia increases.

“We found a strong and consistent relationship between two particular antibodies and the level of impairment,” said study co-author L. Stephen Miller, professor and director of clinical psychology training in the UGA Franklin College of Arts and Sciences. “The finding brings us closer to our ultimate goal of developing a blood test that can diagnose Alzheimer’s disease or potentially identify if someone is at higher risk for the disease.”

Miller’s co-authors include Jennifer S. Wilson, a former undergraduate student in the UGA Honors program who is now pursing graduate studies at Emory University; Shyamala Mruthinti, research pharmacologist at the VA Medical Center and adjunct professor at MCG; and Jerry Buccafusco, director of the MCG Alzheimer’s Research Center. The team focused on antibodies that the body creates in response to two proteins that are associated with Alzheimer’s disease. One protein, known as amyloid-beta, forms the plaques that are evident in the brains of people with Alzheimer’s upon autopsy. The other protein, known as RAGE, is involved in the normal aging process but is expressed at higher levels in the brains of people with Alzheimer’s.

In a previous study that compared a group of people with Alzheimer’s disease to a healthy control group, Mruthinti and her colleagues found that anti-amyloid beta and anti-RAGE antibodies are significantly higher in the group with Alzheimer’s. The team’s latest study expands on that finding to reveal a direct relationship between severity of Alzheimer’s disease and levels of the two antibodies in the blood.

“Alzheimer’s is an inflammatory disease of the brain, and these two antibodies give us a way to measure that inflammation,” Mruthinti said. “Using them as an early diagnostic marker may allow us to start drug treatment early, when it’s most effective, to increase the patient’s quality of life.”

While optimistic about their findings, the researchers caution that it could still be years before a diagnostic test based on their work is clinically available. The study found that the relationship between the two antibodies and Alzheimer’s severity persists even after controlling for patient age and total antibody levels. To further test the strength of the relationship, the researchers are now working with a sample that controls for other factors that have the potential to influence levels of the two antibodies, such as diabetes and heart disease. Buccafusco and his colleagues are also working to decrease the cost and time involved in the test.

“We’re in the process of trying to reduce the test to a one-day procedure, whereas right now it takes three to four days,” Buccafusco said. “But even now, our test is orders of magnitude cheaper than having people come in every few months to get a functional MRI or PET scan to try to discern brain plaques.”

The team is targeting the two proteins themselves as a possible treatment for Alzheimer’s disease. Mruthinti explains that, individually, amyloid-beta and RAGE proteins don’t provoke an immune response. The trouble begins when the two bind and the immune system attacks, resulting in constant state of inflammation that damages the brain. The researchers recently developed a way to measure levels of amyloid beta-RAGE complex, and preliminary data using transgenic mice that express Alzheimer’s symptoms suggest that an antigen they created to boost the body’s natural immune response to the complex can reduce the formation of the brain plaques.

“The amyloid beta-RAGE complex cuts off the connections between neurons,” Mruthinti explained, “but our hope is that we can protect those connections by preventing those plaques from forming.”

The research was funded by a Merit Review Award from the Veterans Administration to principal investigator Mruthinti and by the Medical College of Georgia Alzheimer’s Research Center.

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UGA Research Shows Need for Vitamin Supplements among Georgia's Elderly

A new study by University of Georgia researchers shows that despite the availability of fortified foods, many older adults suffer from deficiencies of vitamin D, calcium and B12, which are critical for optimal bone, blood and nervous system health.

The research grew out of the authors' interest in providing scientifically sound health promotion programs at more than 200 senior centers across Georgia that help prevent malnutrition and provide nutritionally balanced meals to low-income elderly. Published in the Journal of Nutrition for the Elderly, the study notes that nutrient deficiencies make the elderly more vulnerable to chronic health problems such as osteoporosis, anemia and cognitive impairment.

"We always say 'food first' because eating a wide variety of foods provides the best source of minerals, vitamins and other nutrients," said Mary Ann Johnson, professor of foods and nutrition in the UGA College of Family and Consumer Sciences and coauthor of the study. "But people don't always eat a balanced diet, and vitamin supplements are convenient, relatively inexpensive and some have shown definite benefits in preventing or reducing the risks of chronic disease."

Johnson and study coauthors Joan Fischer, associate professor of nutrition, and research assistant Sohyun Park, said that among those surveyed, more than 60 percent of adults aged 60 or older take some type of dietary supplement; 40 percent take multivitamin and mineral supplements. Yet many were also confused about which vitamin supplements are beneficial.

That's understandable, they said, given conflicting research studies. While the use of multi-vitamin and mineral supplements do increase the blood concentration of nutrients, researchers often can't demonstrate specific health benefits from their use.

In fact, several recent vitamin studies only muddy the waters about the benefits of supplements. In November 2008, scientists released findings of a large clinical trial of nearly 15,000 male doctors who took vitamins C and E for a decade, showing no benefits in reducing cancer rates. Another recent study found that vitamins C and E don't lower heart disease rates. And last October, a third major clinical trial--looking at whether vitamin E and selenium protect men against prostate cancer-- ended early when it was clear that neither nutrient would reduce cancer risks.

But the UGA researchers say the benefits of taking certain supplements, especially calcium and vitamin D, are well-documented. Vitamin D, a fat-soluble vitamin, helps the body absorb calcium. It is present in significant amounts in fish and fortified milk, but very few other foods. Vitamin D is also known as the "sunshine vitamin" because it can be manufactured by the body when exposed to sunshine. However, as people age their skin starts to lose this ability to make vitamin D.

"We found that milk consumption varies widely in older adults," said Fischer, "and some elderly people avoid dairy products altogether because of the fat in whole fat products--or because they have trouble digesting milk products. But there is strong evidence that vitamin D and calcium supplements improve overall bone health and prevent bone fractures."

Calcium, essential for strong bones, is also important for normal heart and muscle function--and it helps the blood clot normally. The body uses and loses calcium every day through sweat, urine, feces, hair, nails and skin. It's replaced by calcium-rich foods in the diet, including milk and dairy products, kale, collard greens and foods fortified with calcium, such as some brands of orange juice. But when the body doesn't get enough, it pulls calcium from skeletal bones to carry out the more critical demands of the heart, nerves and major muscles.

B12, a water soluble vitamin, promotes the normal functioning of the brain and nervous system--and facilitates the formation of blood and new cells throughout the body. Good dietary sources include milk products, meat, poultry, fish and fortified breakfast cereals. After age 50, people don't absorb vitamin B12 as efficiently and must guard against a deficiency.

"By the time people reach their elder years, the cumulative effects of lifestyle really start to show, good or bad," said Johnson. "Part of the problem is that we need research that demonstrates the costs of poor nutrition and poor lifestyle. For example, many cases of diabetes and its complications are preventable. Nutrition is a science, but it doesn't get the attention it deserves. We're making progress, but we have a long way to go."

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UGA Study: Even Occasional Smoking can Impair Arteries

Even occasional cigarette smoking can impair the functioning of your arteries, according to a new University of Georgia study that used ultrasound to measure how the arteries of young, healthy adults respond to changes in blood flow.

“Most people know that if they have a cigarette or two over the weekend that it’s not good for their arteries,” said study co-author Kevin McCully, a professor of kinesiology in the UGA College of Education, “but what they may not be aware of—and what our study shows—is that the decrease in function persists into the next week, if not longer.”

Previous studies have shown reductions in the arterial health of people who smoke regularly, McCully said, but what’s surprising about his finding is that the study subjects were occasional smokers (less than a pack a week) who had not smoked for at least two days before their ultrasound. The study, which appears in the early online edition of the journal Ultrasound in Medicine and Biology, found that the arteries of occasional smokers were 36 percent less responsive to changes in blood flow than non-smokers.

McCully explained that the healthier an artery is, the more responsive it is to changes in blood flow. A reduction in responsiveness, known as impaired flow-mediated dilation, is an early sign of arterial damage that often foreshadows cardiovascular disease. The researchers recruited 18 college students for their study, half of whom were non-smokers. The other half smoked less than a pack a week and had not smoked for at least two days before undergoing testing. The researchers measured the responsiveness of the participants’ arteries by inflating a blood pressure cuff around their non-dominant arm to reduce blood flow to the forearm for various durations up to 10 minutes. The researchers then rapidly deflated the cuff and measured how well the main artery in the forearm responded to the sudden increase in blood flow.

“We wanted to determine whether occasional smoking can impair flow-mediated dilation and found that repeated bouts of cigarette smoking—even if classified as occasional—appear to increase the risk for developing cardiovascular disease in otherwise healthy, young people,” said lead author Lee Stoner, a former UGA doctoral student and now a researcher at Christchurch Hospital in New Zealand.

After the occasional smokers underwent their initial test, they smoked two cigarettes and had their arteries re-examined. The researchers found that smoking dropped their arterial responsiveness by another 24 percent compared to before they smoked.

McCully acknowledged that the study used a relatively small sample size and said that further research is needed to determine if the impaired arterial function is a relatively short-term phenomenon or causes long-term damage. But he said that in light of his findings, people shouldn’t assume that smoking occasionally allows them to avoid the harmful effects of tobacco.

“We saw a definite effect of cigarettes on the arteries, even in young people who you would expect to be healthy,” he said.

By Sam Fahmy
University of Georgia

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UGA's Center for Tropical and Emerging Global Diseases to Host Global Health Research Symposium

The University of Georgia’s Center for Tropical and Emerging Global Diseases will host an international research symposium, “Global Health through Research,” on Sept. 19 and 20 at the Georgia Center for Continuing Education Conference Center and Hotel on the UGA campus. The symposium will be held in conjunction with the 18th Annual Molecular Parasitology/Vector Biology Symposium.

To recognize and help celebrate the center’s tenth anniversary, symposium organizers planned the event as an expanded version of their traditional annual meeting. The program will feature ten of the world’s most prominent researchers who study human parasites and the insect vectors that spread them.

“This will be an exciting conference packed with cutting-edge presentations from the best investigators in the field,” said Boris Striepen, a symposium organizer. “We are also eager to present the outstanding work of UGA students and postdoctoral researchers to this highly accomplished audience.”

Scheduled speakers will discuss a wide range of scientific issues, including how parasites conquer their hosts, secure nutrients, and outwit the immune system to cause deadly diseases. Wielding sophisticated tools of molecular biology and genome science, these researchers work to reveal the parasites’ tricks and to develop urgently needed drugs and vaccines. Diseases to be discussed include malaria, sleeping sickness, leishmaniasis and several other diseases associated with AIDS.

The Center for Tropical and Emerging Global Diseases is a university-wide, interdisciplinary center established in 1998 to foster research, education and service related to tropical and emerging infectious diseases. Over the past decade CTEGD has grown into one of the nation’s preeminent institutes for tropical disease research. The center’s 18 members include faculty from eight UGA departments and four colleges. The center also benefits from the participation of adjunct faculty from the Centers for Disease Control and Prevention in Atlanta.

by Helen Fosgate
University of Georgia

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UGA Kinesiology Researcher Receives $1.7 Million NIH Grant to Explore Use of Electric Stimulation of Muscles as Tool Against Diabetes

University of Georgia researchers who have developed a treatment that improves blood sugar levels in paraplegics, reducing their risk of becoming diabetic, are now asking if the same method can help treat or even reverse the condition in paraplegics who already have diabetes.

Kevin McCully, a professor in the College of Education’s department of kinesiology, is principal investigator of the study which has received a $1.7 million grant from the National Institutes of Health to follow up on a discovery that may offer a solution to people with paralysis who developed diabetes as a result of their injury.

“We’re pretty excited about this. It’s an important health problem.” said McCully, director of the Exercise Vascular Biology Laboratory in the Ramsey Center.

The hopeful results were an unexpected discovery made by McCully and the late UGA Distinguished Research professor Gary Dudley. The scientists initially used electrical stimulation as a way of exercising leg muscles that their subjects could no longer flex, or even feel, believing that strength training can help people with complete paralysis—those who are completely unable to move their legs—improve their cardiovascular health.

“What we found was yes indeed, we could resistance train them,” said McCully. “Their muscle size increased and their blood flow improved.”

But while monitoring the subjects’ oral tolerance to glucose, using a simple test that can show whether a person is likely to develop diabetes, the researchers made an exciting discovery. They found that the strength training dramatically improved glucose sensitivity, greatly reducing the study participants’ chance of getting diabetes.

Improvements in medical care have made it possible for paraplegics to live much longer than they would have in the past. However, living longer lives means they also must wrestle with common health problems other populations often face.

Diabetes, the sixth leading cause of death in the United States, is related to the pancreas, an organ near the stomach that produces a hormone called insulin. In people with diabetes, the pancreas doesn’t produce enough insulin or their bodies aren’t able to use the insulin properly, which can lead to serious complications such as kidney failure, heart disease and blindness.

“People who are paralyzed are three to four times more likely to become diabetic,” said McCully. “So it’s an important health problem, and our continuation is to follow up on that.”

The high-tech treatment is surprisingly simple. By attaching electrodes to paraplegics’ thighs from small battery-operated current generators and sending a mild electric current into the legs, the nerve endings are stimulated, generating force and expending energy the same way a muscle would contract in a non-paralyzed person.

The upcoming study is part of a nearly decade-long collaborative effort between UGA and the Shepherd Spinal Center in Atlanta. College of Education faculty members Lesley White, an associate professor in kinesiology, and Stephen Olejnik, a professor of educational psychology, are co-investigators.

Dudley forged an alliance between UGA and the Shepherd Center in the late 1990s, where he himself was taken for rehabilitation following a catastrophic car accident in 2002. A year later, he was back in the classroom, defying predictions that he would live in a nursing home the rest of his life. Dudley worked at NASA and the University of Ohio before joining the UGA faculty in 1993, where he was named a Distinguished Research Professor and awarded the prestigious Creative Research Medal. He passed away in 2006 following a long battle with cancer.

McCully, who studies effects of aging and disease on muscle metabolism and functional capacity, was named a Fellow of the American Academy of Kinesiology and Physical Education in 2007. He joined the UGA faculty in 1999 from the Medical College of Pennsylvania and Hahnemann University. He received his Ph.D. in physiology from the University of Michigan.

By Catharin Shepard

UGA Researchers Discover Mechanism that Explains How Enzyme Crucial to Cancer Growth Winds Up on Ends of Chromosomes

Human cancer cells divide and conquer. Unless physicians can control that division with surgery, chemotherapy or radiation, the wildly dividing cells will eventually destroy a person’s life.

Researchers have known for some time that an enzyme called telomerase is crucial to cancer’s progress. Now, for the first time, researchers at the University of Georgia’s Franklin College of Arts and Sciences have shown a mechanism that explains how two essential components of human telomerase—normally active only in early prenatal development but turned back on during cancer growth—are “recruited” from distinct sites in the cell to the telomere, an area at the end of a chromosome that normally protects it from destruction.

“Telomerase is reactivated in more than 90 percent of human cancers,” said Michael Terns, professor of biochemistry and molecular biology and genetics at UGA, “and the fact that telomerase keeps these telomeres growing when it should be inactive is crucial for the proliferation of cancer. That makes telomerase a very promising target for a potential drug to stop cancers from spreading.”

The research was just published in the journal Molecular Biology of the Cell. Other authors on the paper were Rebecca Terns, a senior research scientist also in UGA’s department of biochemistry and molecular biology (Michael and Rebecca Terns are a husband-wife team); Rebecca Tomlinson, a former doctoral student in the Terns Lab; Eladio Abreu, a current graduate student in the Terns lab; Tania Ziegler, also a former member of the Terns lab, now pursuing an M.D. degree; Hinh Ly of Emory University; and Christopher Counter of Duke University Medical Center. Rebecca and Michael Terns are also members of the University of Georgia Cancer Center.

The two essential components of human telomerase are telomerase RNA and telomerase reverse transcriptase. They are “recruited” to telomeres during what is called the “S phase” (for synthesis) of the cell cycle when DNA replication or synthesis occurs.

“What we have found is that during the remainder of the cell cycle, telomerase RNA is found primarily in rather mysterious and, until recently, little-understood structures called Cajal bodies,” said Rebecca Terns. “Though science has known about Cajal [pronounced Ca-HAHL] bodies for more than a hundred years, what we have discovered is that the localization of telomerase RNA to Cajal bodies and telomeres is specific to cancer cells where telomerase is active.”

The new research shows for the first time that the trafficking of telomerase RNA to both telomeres and Cajal bodies depends on the presence of telomerase reverse transcriptase.

The Terns lab took advantage of the differences between normal and cancer cells of many kinds to better understand the trafficking of telomerase RNA.

“We examined a variety of factors that differ between normal and cancer cells in order to identify factors that impact human telomerase localization,” said Michael Terns. “Our results indicate that human reverse transcriptase is a key determinant in human telomerase trafficking and is essential for the localization of telomerase RNA both to Cajal bodies and telomeres.”

While all this jargon-filled science may sound difficult to understand, the discovery could lead to new ways to attack cancers by blocking their ability to grow. While that is years down the road, the new understanding of how this crucial biological action in the human body takes place will at the very least open new avenues of investigation into why and how cancer cells continue to grow and take the human toll they do every day.

The research was primarily supported by grants from the National Cancer Institute of the National Institutes of Health.

By Philip Lee Williams

UGA Research May Lead to Safer, More Effective Gene Therapy

The potential of gene therapy has long been hampered by the risks associated with using viruses as vectors to deliver healthy genes, but a new University of Georgia study helps bring scientists closer to a safe and efficient gene delivery method that doesn’t involve viruses.

Assistant professor of chemistry Yan Geng and her colleagues in the UGA Franklin College of Arts and Sciences have created a novel synthetic gene vector that packages DNA into well-defined nanostructures that allow it to efficiently deliver genes without triggering immune responses. The study, primarily carried out by doctoral student Jennifer Haley, appears in the June issue of the journal Molecular BioSystems and also may have implications for cancer treatment and vaccine development.

“We’ve developed a very versatile approach to creating synthetic gene delivery vectors,” said Geng, a Georgia Cancer Coalition Distinguished Scholar and a researcher in the UGA Cancer Center. “Our approach is relatively simple – using simple chemical reactions to create a new class of packaging molecules that wrap up genes on their own – and has the potential to be very useful in real-world, clinical applications.”

Gene therapy involves replacing abnormal, disease-causing genes with normal genes. To do this, genetically modified viruses often are used. The viruses do a remarkable job of inserting the new genes into hosts, Geng said, but they’re inherently dangerous. So while the use of viruses as gene delivery vectors has been efficient, it also has led to unexpected and tragic complications, some of which were fatal. Synthetic vectors, which use synthetic molecules to package genes, are generally safer than viral vectors, Geng said. The downside is that they’re not nearly as efficient. For millions of years, viruses have evolved into a small size, a rich variety of shapes – spherical, disk-like, and sometimes long filaments, and sophisticated mechanisms to facilitate the easy entrance of their DNA into cells.

“In nature, viruses are precisely self-assembled by their coating proteins and genome,” Geng said. “We have to learn from nature and engineer a safer yet efficient gene delivery system for medical use.”

Synthetically packaging long strands of DNA into compact, small structures has long been a challenge, but Geng’s team has developed a unique combinative self-assembly method that allows scientists to control precisely the size and shape of the vector. The Geng team synthesized small peptides – which are short chains of amino acids – that bind to genes and emulate natural proteins to minimize potential immune reactions. The researchers then attach the small peptides onto a biocompatible polymer scaffold to create a clustered effect. The clustered peptides of the combined molecule will automatically assemble with DNA, while the polymer wraps around the assembly, creating a protective shell. The researchers have discovered that the assembly process is extremely sensitive to the clustered arrangement of the gene-binding peptides. To change the shape and size of the vectors, the researchers simply change the attachment density of the peptides on the polymer scaffold, resulting in shapes that vary from spherical to donut shaped to long filaments.

“These gene vectors also can be further conjugated with targeting molecules, which will allow us to deliver the right genes to the right spot in our body,” Geng added.

With the synthesis of the vector complete, the scientists now plan to assess how effective it is in integrating genes into cancer cells. Geng said her ultimate goal is to use tumor-suppressor genes to treat cancer. Another possibility is to use the synthetic vectors to introduce genes that boost the immune system.

“Our research is still at an early stage,” Geng said, “but we’ve developed a very promising system.”

The research was funded by the UGA Research Foundation and the Georgia Cancer Coalition.

By Sam Fahmy