DukeHealth.org: Duke Health News

Molecular Pathways Linked to Sex, Age Affect Outcomes in Lung Cancer

Tue, 09 Feb 2010 00:00:00 -0500

The biology of lung cancer differs from one patient to the next, depending on age and sex, according to scientists at Duke University Medical Center.

The findings, appearing in the Journal of the American Medical Association, may help explain why certain groups of patients do better than others, even though they appear to have the same disease.

“Our study supports two key findings: First, the biology of lung cancer in women is dramatically different from what we see in men. Women, in general, have a less complex disease, at least in terms of the numbers of molecular pathways involved. We also discovered that there is a subset of elderly patients would probably benefit from treatments that we’ve normally reserved for younger patients,” says Anil Potti, MD, an oncologist in the Duke Institute for Genome Sciences & Policy (IGSP), and the senior author of the study.

Potti says that in the past, physicians have had to rely on very rough measures to categorize patients’ lung cancers, factors such as the size of the tumor, the tissue type and the degree to which the cancer had spread.

“But this new information tells us that we can analyze patients’ disease much more discretely,” says Potti. He says the information could also be used to enrich the selection process in clinical trials designed to evaluate new drugs aimed at specific molecular targets.

Physicians have long observed that over time, women with lung cancer tend to do a little better than men, and that younger patients do better than older ones. Potti found that women tend to have only a few cancer-promoting pathways activated in their tumors, where men may have twice as many.

Potti and a team of researchers in the IGSP studied clinical data and accompanying genomic information obtained from tumors of 787 patients with predominantly early stage non-small cell lung cancer (NSCLC), the most common form of the disease. They gathered tumor samples and corresponding microarray data showing which genes were activated in the tumors, then selected twelve of the most common molecular pathways that become dysregulated in NSCLC.

The goal was to identify any patterns linking the pathways to age, sex and time to recurrence. They sorted the patients by age and sex and then again into low- and high-risk groups, based on five-year, recurrence-free survival.

They found that certain molecular pathways were more frequently activated in some groups than others and that certain pathway patterns were associated with better long-term survival in patients with lung cancer. Specifically, they found that:

High-risk patients -- those with the shortest time to recurrence -- were significantly more likely to have increased activation of the pathways responsible for tumor metastasis and necrosis, when compared with low-risk patients.
High-risk patients 70 or older were found to have higher activation of pathways regulating blood supply and invasiveness.
In comparing high-risk women to high-risk men, they found that men were more likely to have a much more complex pattern of multiple pathways being activated than women with the same type of lung cancer.

The study also identified a subset of patients over age 70 who had a low-risk profile, meaning the molecular pathways activated in their tumors would likely give them a better chance at long-term survival. Potti says that’s important because people over age 70 are generally not included in many clinical trials and physicians often hesitate to offer them the option of conventional chemotherapy.

“The thinking has been that they may not withstand the treatment or benefit from it much. But now we know that it probably makes sense to consider treating this population, by risk-stratifying the disease,” says Potti.

Potti says it is likely that there are additional cancer-promoting pathways that are involved in the development and progression of NSCLC and adds that these findings must be validated in other studies. But he said the set of 12 known oncogenic pathways they chose to study are significant “because we already have drugs that can regulate many of them.”

“People still don’t realize how bad a disease this is,” says Jeffrey Crawford, MD, a study co-author and the chief of medical oncology at Duke. “Lung cancer kills more than 150,000 patients each year in the U.S. -- more than breast, prostate, colon and ovarian cancer combined. Unfortunately, there is a patient dying from lung cancer every three minutes in this country. So being able to better understand the disease and stratify patients by their individual molecular profiles means we can do a much better job pairing the right drug with the right patient.”

The study was funded by grants from the Emilene Brown Cancer Research Fund, the Harold and Linda Chapman Lung Cancer Fund, the Jimmy V Foundation, the American Cancer Society and the National Cancer Institute.

Duke colleagues who contributed to the study include lead authors William Mostertz, Marvaretta Stevenson, Chaitanya Acharya, Isaac Chan, Kelli Walters, Wisut Lamlertthon, William Barry, Jeffrey Crawford and Joseph Nevins.

New Duke Clinical Research Unit to Conduct Groundbreaking Translational Research

Thu, 04 Feb 2010 00:00:00 -0500

A new state-of-the-art clinical research facility that could transform the framework for the clinical development and evaluation of investigational drugs and medical devices, as well as provide a new way of studying a wide range of emerging -- and longstanding -- medical research questions, opened today at Duke University Medical Center.

The Duke Clinical Research Unit (DCRU) will become one of just a handful of hospital-based, early phase research units in the U.S. that will apply a variety of cutting-edge "-omics" (genomics, proteomics and metabolomics) technologies, as well as advanced imaging, cell therapy, biobanking, immune monitoring, and one of the world’s only EchoMRI systems, to measure the physiological effects of medical interventions and better understand the biological causes of diseases or conditions.

In the case of early phase studies of investigational drugs or devices, the unit is uniquely able to generate a much more intensive and broader array of data at the initial proof-of-concept or "first-in-human" stage of clinical development.

Generating exponentially greater data down to the molecular level at this preliminary stage of clinical development will provide more comprehensive insights to inform development decisions than are currently available in traditional early phase studies.

"The established clinical trials process is in need of an overhaul as evidenced by the long development process and the unacceptably high number of treatments found to be detrimental, even after they reach the market," said Rob Califf, MD, vice chancellor for clinical research at Duke University and director of the Duke Translational Medicine Institute.

"The application of a novel systems biology and molecular medicine approach to early phase studies represents the kind of innovation that could result in much-needed fundamental change."

In addition to assessing the viability of new drug and device candidates, the DCRU will be able to conduct studies that could range from those designed to identify and validate novel biomarkers of disease to studies that can shed light on the biological processes involved in certain everyday activities or behaviors associated with medical risks. This work will be conducted in collaboration with a host of research partners, including the pharmaceutical and medical device industry, foundations and government entities.

One of the first studies underway in the DCRU is a study designed with the goal of personalizing aspirin therapy and ultimately enhancing aspirin’s ability to prevent heart disease and stroke, two leading causes of global morbidity and mortality.

Millions of people use aspirin to protect their heart, yet doctors have no way to accurately identify those who are receiving the drugs beneficial effect to prevent a heart attack or stroke. The results of this National Institutes of Health-funded study will allow doctors, for the first time, to understand which patients are 'sensitive' and which are 'resistant' to aspirin’s blood thinning effects and to tailor therapy accordingly.

"In addition to opening a new door to faster and more accurate clinical research, we will be tackling research questions that have been overlooked and unanswered for decades," Califf said. "After 100 years of use, Duke researcher Geoff Ginsburg, MD, PhD, is leading a study to better understand aspirin’s effect on the body and optimal dosing.”

Industry statistics show that advancing a new therapy through the clinical trials process is a long and expensive endeavor, with only about 11 percent of investigational therapies ultimately reaching patients. Furthermore, one in four compounds fails even after completing registration trials, resulting in a loss of billions of dollars while also exposing patients to agents with potential risks.

"Unlike the typical early phase study designed to obtain limited information about the dosing, safety, and toxicity of a drug by giving it to healthy people, the unit employs an innovative approach that utilizes cutting-edge technologies and disease-specific populations to better understand disease and predict drug response," said John McHutchison, MD, program director of the DCRU and associate director of the Duke Clinical Research Institute.

"To achieve this, DCRU brings together the clinical expertise and scientific leadership of an academic medical center with the operational capabilities of a full-service contract research organization."

The DCRU, in collaboration with the recently announced Medanta Duke Research Institute (MDRI) in New Delhi, India and the Duke-affiliated early phase research unit in Singapore, comprise an international network designed to accelerate clinical research and development, as well as evaluation of human biology, diseases, drugs and devices.

The collaboration will unlock the potential for undertaking simultaneous early phase clinical studies in three countries with diverse populations.

"Our goal is to advance clinical trial methodology and translational medicine in the interest of improved healthcare delivery," said McHutchison, who will also be leading the development of the global network of proof of concept units.

Unlike other clinical research organizations, the DCRU is in a hospital-based setting, with access to extensive patient populations, paired with the clinical expertise and resources needed to oversee their care. It is one a of few research units in the U.S. with access to disease-specific pediatric, adult, and geriatric populations. The unit also provides immediate, round-the-clock access to an on-site, full-scale emergency response team.

Specialized facilities are available for both adults and children, including a 30-bed 17,000-square-foot adult unit and a 13,000-square-foot pediatric unit with six confinement beds and two infant family rooms.

Duke Medical Team Heads to Haiti

Wed, 03 Feb 2010 00:00:00 -0500

A team of medical professionals from Duke University Medical Center is traveling to Haiti on Friday to provide much-needed medical support to a Partners in Health (PIH) hospital in Cange, a city about two hours from Port au Prince.

Their goals are two-fold: to meet the ongoing demand for a variety of surgical procedures, post-op care, and specialized wound care; and to help reinitiate medical care and treatment of people with serious chronic infectious diseases such as tuberculosis and HIV/AIDS.

"We were immediately ready to mobilize a team to provide medical assistance in Haiti; however, given the chaos on the ground and the need for coordination there, we made a decision to work through a trusted partner in PIH which was already in Haiti and who we know would identify the urgent medical needs and provide the specific logistics support for our relief effort," said Victor J. Dzau, MD, Chancellor for Health Affairs at Duke and CEO, Duke University Health System.

"The request by PIH to assist them in this critically important post-acute care phase is magnified as we understand that exhausted emergency surgical teams are beginning to transition out of Haiti and local Haitian physicians are finally in a position to attend to their own situations and tragedies."

Partners in Health, a global health organization led by Duke alum and University Trustee Paul Farmer, MD, PhD, has been providing medical care in Haiti for more than 20 years, "but it was never structured to handle the magnitude of such a large-scale, traumatic event," said Ian Greenwald, MD, chief medical officer of Duke University Health System’s Preparedness and Response Center, and leader of Duke Medicine’s effort.

"They advised us what they needed based on the dynamic needs of their patients, and we assembled a team with exceptional specialized expertise to provide the services and care requested."

The 14-member Duke team includes two general surgeons, an orthopedist, an anesthesiologist, certified nurse anesthetist, an infectious disease physician/internal medicine physician, emergency room physician, wound care nursing specialists, a limb-loss nursing specialist, nurses, and a surgical technologist.

"The public health infrastructure was fragile in Haiti before the earthquake," explains Cameron Wolfe, MD, an infectious disease expert on the Duke team.

"And, Haitian health care providers have had to stop their work to rightfully attend to their own situations and families. We've been asked to work with them to regain management of TB and HIV/AIDS care and work on the problem of infectious disease, including emerging ones like cholera."

"I am proud of the commitment of our staff to make the personal sacrifices necessary to reach out to the people of Haiti," said Dzau. "It is a testament to the character of our faculty and employees and their preeminent commitment to helping others."

In addition to mobilizing this medical team, Duke Medicine has also provided shipments of medical supplies and medicines to Family Health Ministries, a non-profit medical mission organization in Haiti led by Duke faculty member David Walmer, MD, and his wife Kathy.

Duke Community Supports Haiti Relief Efforts

Wed, 27 Jan 2010 00:00:00 -0500

In response to the disaster in Haiti, Duke has launched a central Web site to provide updates and resources to help members of the Duke community support Haiti relief efforts.

The site includes news and announcements, ways to give, and information about volunteer opportunities.

For more information, visit duke.edu/haiti.

Renowned Duke Researcher Wins Frontiers of Knowledge Award

Wed, 27 Jan 2010 00:00:00 -0500

The prestigious BBVA Foundation Frontiers of Knowledge Award in the Biomedicine category goes this year to Robert J. Lefkowitz, MD, James B. Duke Professor of Medicine and Biochemistry and a Howard Hughes Medical Institute (HHMI) investigator at Duke University Medical Center.

This is only the second year the award has been given.

Dr. Lefkowitz’s research has affected millions of cardiac and other patients worldwide. Lefkowitz proved the existence of, isolated, characterized and still studies G-protein-coupled receptors (GPCRs).

The receptors, which are located on the surface of the membranes that surround cells, are the targets of almost half of the drugs on the market today, including beta blockers for heart disease, antihistamines and ulcer medications.

Lefkowitz, a Duke faculty member since 1973, also investigates related enzymes, proteins, and signaling pathways and continues to learn all he can about these pivotal receptors.

"I am surprised, delighted and honored by the award, and am honored to be in the company of Joan Massagué, a fellow HHMI investigator who won last year," said Lefkowitz, who is also a Duke professor of immunology and a basic research cardiologist in the Duke Heart Center.

"While it is a relatively new award, I know it is a very distinguished award, and I am delighted to be the recipient."

The BBVA Frontiers of Knowledge Award in Biomedicine provides the winner a cash prize of 400,000 euros (about $563,400). The award, organized by the BBVA Foundation in partnership with Spain’s National Research Council, was announced at 11 a.m. Madrid time on Jan. 27.

Dr. Lefkowitz is being awarded the prize for the work he has done since the beginning of his career and includes his ongoing studies of GPCRs and other key receptors.

His research group first identified, purified, and cloned the genes for these receptors in the 1970s and 1980s, and revealed the structure of the receptors as well as their functions and regulation. This work facilitated and fundamentally altered the way in which numerous therapeutic agents have been developed.

Lefkowitz is also extremely proud of his mentoring work and of the students and fellows he has worked with over the years, many of whom have gone on to run successful laboratories and uncover their own discoveries about GPCRs and other receptors.

The Biomedicine Award honors contributions that significantly advance the stock of knowledge in the biomedicine field because of their importance and originality.

The BBVA Foundation Frontiers of Knowledge Awards seek to recognize and encourage world-class research at the international level, and are similar to the Nobel Prizes, with an annual total of 3.2 million euros given to deserving winners, because of the breadth of the scientific and artistic areas they have covered during their careers.

A DASH of Exercise and Weight Loss Improves Blood Pressure

Mon, 25 Jan 2010 00:00:00 -0500

Adding exercise and weight loss to the nationally recommended DASH diet (Dietary Approaches to Stop Hypertension) reduced blood pressure equal to rates expected with use of medication alone, according to researchers at Duke University Medical Center.

A study published in the Archives of Internal Medicine found a significant 16-point improvement in blood pressure among patients on the DASH diet who participated in aerobic exercise and were encouraged to lose weight.

Patients who just followed the diet showed an 11-point reduction in blood pressure and the control group who continued their typical lifestyles showed a three-point improvement.

"Not only were we surprised by the magnitude of the blood pressure reductions for people on the DASH diet who lost weight and exercised, but we found that they also improved other important cardiovascular biomarkers," said James Blumenthal, PhD, a psychologist at Duke and lead author of the study.

"Participants who just followed the DASH diet also improved, but not as much as those who also exercised and lost weight."

The DASH diet is included in national guidelines for preventing and treating blood pressure. It emphasizes dietary lifestyle changes instead of weight loss through meals comprised of fruits, vegetables, and low fat dairy foods. Whole grains, poultry, fish, and nuts are encouraged over fats, red meats, sweets and sugared beverages.

The new study is the first to evaluate the effect of the DASH diet among people who selected and prepared their own food and, in some cases, did not lose weight.

Blumenthal said this study is similar to a "real world" experience because most past studies provided food for participants from a pre-determined menu.

"The 'pre-hypertensive' and mildly hypertensive individuals included in the study represent a significant percent of our population," Blumenthal said. "If we can intervene and make changes at this critical stage in the process, we may have the opportunity to prevent future heart attacks and strokes."

Participants included 144 people who were overweight or obese, had elevated blood pressure (systolic: 130-159 and diastolic: 85-99) and were not taking medication. They were randomly assigned to one of three groups: the DASH diet alone, the DASH diet in combination with aerobic exercise plus small group sessions about weight loss techniques, or no change in diet and exercise habits.

After four months, people in the exercise and weight management group lost approximately 19 pounds on average while the other two groups lost minimal weight or gained weight.

In addition to blood pressure differences, the research team also observed changes to the structure and function of the heart. People on the DASH diet who lost weight and exercised had decreased artery stiffness and a reduced thickening in the left ventricle of the heart.

"While blood pressure is a marker of disease risk, the other biomarkers we evaluated are consequences of exposure to high blood pressure, which are important independent predictors of cardiovascular morbidly and mortality," Blumenthal said.

After the four month study period, the research team introduced the DASH diet concept to all participants. They are continuing to follow these individuals to monitor the extent to which they embrace the diet and the resulting impact on blood pressure and other disease markers.

The study was funded by the National Heart, Lung, and Blood Institute.

Study co-authors include Michael Babyak, Alan Hinderliter, Lana Watkins, Linda Craighead, Pao-Hwa Lin, Carla Caccia, Julie Johnson, Robert Waugh and Andrew Sherwood.

New Routes Through Duke Clinic

Mon, 25 Jan 2010 00:00:00 -0500

Click to enlarge.

Beginning Monday, February 8, the way you get from Duke Clinic to Duke University Hospital is going to change.

When the South Concourse at Duke Clinic's north end opens in early February, it will be the first step to improve the way patients, visitors, and staff move between clinical facilities.

On Level 1 of Duke Clinic, the concourse will be accessed near Clinic 1A. On Level 2, the concourse will be accessed near the oncology treatment center.

Click to enlarge.

The concourse is a two-story extension of Duke Clinic that replaces the walkway currently accessed through the old PRT lobby in the clinic’s lower level.

Corridor traffic will no longer move to the lower level of Duke Clinic to reach the walkway. Instead, the main corridors of Duke Clinic’s Level 1 and Level 2 will lead to the new concourse. Stairs and elevators at the concourse’s end will then lead down to the walkway to Duke University Hospital.

Click to enlarge.

Travelers moving south from Duke University Hospital will use the walkway and take stairs or elevators up to enter Duke Clinic.

Enhanced signage and strategically positioned Duke Patient & Visitor Relations personnel will help guide patients, family members, faculty, and staff through Duke Clinic to the new concourse segment and then to the walkway to Duke University Hospital during the transition.

Download a map of the new routes (PDF).

Low-Carb Diet Effective at Lowering Blood Pressure

Mon, 25 Jan 2010 00:00:00 -0500

In a head-to-head comparison, two popular weight loss methods proved equally effective at helping participants lose significant amounts of weight.

But, in a surprising twist, a low-carbohydrate diet proved better at lowering blood pressure than the weight-loss drug orlistat, according to researchers at Veterans Affairs Medical Center and Duke University Medical Center.

The findings send an important message to hypertensive people trying to lose weight, says William S. Yancy, Jr., MD, lead author of the study in the Jan. 25 Archives of Internal Medicine, and an associate professor of medicine at Duke. "If people have high blood pressure and a weight problem, a low-carbohydrate diet might be a better option than a weight loss medication."

Yancy added, “It’s important to know you can try a diet instead of medication and get the same weight loss results with fewer costs and potentially fewer side effects.”

Studies had already indicated that a low-carbohydrate diet and prescription-strength orlistat combined with a low-fat diet are effective weight loss therapies.

But the two common strategies had not been compared to each other, an important omission now that orlistat is available over-the-counter. In addition, few studies provide data on these treatments for overweight patients with chronic health issues.

That’s what made these findings particularly interesting, says Yancy, a staff physician at the Durham VA where the research was conducted. The 146 overweight participants in the year-long study had a range of health problems typically associated with obesity -- diabetes, high blood pressure, high cholesterol, and arthritis.

"Most participants in weight loss studies are healthy and don’t have these problems," he said. "In fact they are often excluded if they do."

The average weight loss for both groups was nearly 10 percent of their body weight. "Not many studies are able to achieve that," says Yancy, who attributes the significant weight loss to the group counseling that was offered for 48 weeks.

In fact, he says "people tolerated orlistat better than I expected. Orlistat use is often limited by gastro-intestinal side effects, but these can be avoided, or at least lessened, by following a low-fat diet closely. We counseled people on orlistat in our study fairly extensively about the low-fat diet."

In addition to achieving equal success at weight loss, the methods proved equally effective at improving cholesterol and glucose levels.

But Yancy said it was the difference in blood pressure results that was most surprising.

Nearly half (47 percent) of patients in the low-carbohydrate group had their blood pressure medication decreased or discontinued while only 21 percent of the orlistat plus low-fat diet group experienced a reduction in medication use.

Systolic blood pressure dropped considerably in the low-carbohydrate group when compared to the orlistat plus low-fat diet group.

"I expected the weight loss to be considerable with both therapies, but we were surprised to see blood pressure improve so much more with the low-carbohydrate diet than with orlistat," says Yancy, who says the mechanism is unclear.

"While weight loss typically induces improvements in blood pressure, it may be that the low-carbohydrate diet has an additional effect." That physiologic effect may be the subject of future studies.

The bottom line, says Yancy, is that many diet options are proving effective at weight loss. But it’s counseling patients on how to best follow the options that appears to be making the biggest impact.

"It is clear now that several diet options can work, so people can be given a choice of different ways to lose weight. But more importantly, we need to find new ways to help people maintain their new lifestyle."

This study was funded by the Department of Veteran Affairs.

Rare Genetic Variants Create "Synthetic" Genome-Wide Signals of Disease Risk

Mon, 25 Jan 2010 00:00:00 -0500

Scientists at Duke University Medical Center say they are now convinced that rare genetic variants -- as opposed to more common ones -- lie at the heart of the genetic component of most common diseases.

The finding, stemming from a series of simulation studies, challenges common interpretations of a multitude of genome-wide association studies (GWAS) that have identified thousands of single-DNA letter changes associated with greater risk of common diseases such as cancer, heart disease, and diabetes.

It may also hold important implications for understanding the underlying architecture of human disease.

Over the past several years, the research community has used tests sensitive enough to detect single-letter differences in DNA (called SNPs) to zero in on common human gene variants and their relationship to disease.

Although thousands of significant associations have been identified -- some of which led Science Magazine to declare human genetic variation "the discovery of the year" in 2007 -- the precise genetic changes responsible for these observations have rarely been found.

"It may be because we have been looking in the wrong place,” says David Goldstein PhD, director of the Center for Human Genome Variation in the Duke Institute for Genome Sciences & Policy (IGSP).

Goldstein has long argued that rare, more powerful genetic variation lies in more remote stretches of the genome that GWA studies don’t cover.

In GWA studies, researchers compare what happens to people who carry the alterations to those who do not carry them. The SNPs themselves aren’t necessarily seen as the causative agents of disease but instead point to a region in the genome -- generally one close by -- where genetic alteration causing the disease might reside.

GWA studies are driven by the notion that finding common variation in specific diseases would point to the specific genes at fault and eventually to corrective targeted therapies and a new era of personalized medicine.

"The trouble is, that just hasn’t happened," says Goldstein. "Of course, it is still early and there have been successes. But for most common diseases, the common variants implicated account for only a small proportion of the genetic component. We are now pretty sure that much of the so called ‘missing heritability’ lies within the huge class of relatively or very rare genetic variants which were not represented in previous studies."

Goldstein, along with lead author Samuel Dickson, PhD, a bioinformatician in the IGSP, simulated case-control studies with sample sizes between 2,000 and 6,000 subjects by using simulated genealogical trees to create a realistic spread of variants across one section of a chromosome.

They then used statistics and computer modeling to assess the possibility that a common variant, like those used in GWA studies, would be associated with a disease caused by one or more rare variants in the region.

They found that about a third of the simulations revealed an association with a common variant. They also found that these "synthetic" associations grew stronger as the number of rare variants increased and the relationships remained stable even when computer modeling allowed for chromosomal recombination -- mimicking what happens in the real world over time.

"Basically we showed that not only is it possible that rare variants are behind many of the results of recent findings, but that there are likely to be many more to be found as researchers shift their focus to methods that will find rare variants," says Dickson.

Researchers say their findings are supported by real data from patients with sickle cell disease and a genetically linked form of hearing loss, two disorders representing the possible extremes of synthetic association.

Sickle cell anemia is caused by mutations in one gene. It occurs in one in every 600 African Americans in the U.S. In comparison, hearing loss is a complex disorder affecting one in every 1,000 newborns in the U.S. that involves more than two dozen genes and hundreds of harmful mutations in those genes.

The scientists ran GWA studies among a small number of cases and thousands of controls for both diseases. They found that common gene variants in the region showed genome wide significance, even though the only causal sites were known to be rare variants with a much bigger impact on disease, as predicted by the computer simulations.

"This tells us that we will surely need to turn to more comprehensive whole genome sequencing studies of more carefully selected subjects if we want to discover more meaningful relationships between genetic variation and disease," says Goldstein.

"While such studies are undoubtedly more complex, expensive and time-consuming, we really have no choice if we want to deepen our knowledge about the genetic underpinnings of human disease."

Coauthors include Kai Wang, PhD; Ian Krantz, MD; and Hakon Hakonarson, MD, PhD, from Children’s Hospital of Philadelphia.

Compounds That Help Protect Nerve Cells Discovered by Duke Team

Wed, 20 Jan 2010 00:00:00 -0500

Scientists at Duke University Medical Center have found some compounds that improve a cell's ability to properly "fold" proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.

Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases.

The Duke team has identified many new chemicals that activate a master regulator to increase the supply of "protein chaperone" molecules that help fold proteins properly.

The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.

They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.

Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington’s and Parkinson’s diseases. This work provides a new approach to address the root cause of these diseases -- protein misfolding.

Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.

“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,” said senior author Dennis J. Thiele, PhD, Professor of Pharmacology and Cancer Biology.

“We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery."

The research was published in the Jan. 19 online issue of PLoS Biology.

Lead author Daniel Neef, PhD, says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene.

These yeast, however, still weren’t able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active.

The team put these "humanized yeasts" into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying.

"Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked," Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.

"The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans," Thiele said.

"These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington’s, Alzheimer’s and Parkinson’s disease."

The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).

"We enhanced the cells’ viability by four or five times by pre-treating them with this molecule," Neef said. "Otherwise, the cells would have died."

They used fruit flies with Huntington’s disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly’s food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly’s stomach into its circulation and cross a barrier to the fly brain.

In the key experiment, the Huntington’s disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.

Michelle Turski, now with Stanford University, was a co-author of the study. The work was supported by grants from the National Institutes of Health.

Duke Awarded up to $43 Million to Develop Test for Dirty Bomb/Radiation Exposure

Wed, 20 Jan 2010 00:00:00 -0500

Duke University has received a $3.7 million contract from the Biomedical Advanced Research and Development Authority (BARDA) to develop a rapid and accurate genomic-based diagnostic test that can determine if a person has been exposed to radiation from a dirty bomb or nuclear attack.

In the event that all option years are exercised by the government, Duke University could receive up to $43.6 million from the contract.

"Since 9/11, there has been national concern about the possibility of a terrorist attack in the U.S. involving radiological or nuclear materials. Such an attack could kill or injure hundreds of thousands of people," says John Chute, MD, associate professor of medicine at Duke and principal investigator of the project.

"The problem is that right now, we don’t have any way to rapidly screen thousands of people to determine their level of radiation exposure. Many people who suffer radiation injury can recover and survive if they are promptly and properly treated."

BARDA is part of the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services. It manages Project BioShield and the Public Health Emergency Medical Countermeasures Enterprise, two organizations charged with the development of medical response to pandemic disease and countermeasures for chemical, biological and nuclear attacks.

The award builds upon Chute’s previous collaborations at Duke with Joseph Nevins, PhD, and Nelson Chao, MD, that identified a set of 25 genes in human peripheral blood that are activated in response to radiation.

Chute says that radiation exposure causes a characteristic pattern of expression in those 25 genes and this "signature" can diagnose radiation status with over 90 percent accuracy.

Chute's earlier work was supported by a $25 million grant from the National Institutes of Allergy and Infectious Diseases that established the Duke Center for Medical Countermeasures Against Radiation, now in its fifth year of funding.

The new contract calls for Chute and his team at Duke to further validate the accuracy of the gene profile in animal and human testing.

Collaborators at DxTerity Diagnostics, a biotechnology company based in California, will utilize the Duke gene panel to develop a rapid gene expression test while colleagues at the University of Arizona and Invetech Corporation will design and develop the instrument in which the assay will be performed.

The end product will be a portable, 30-minute test for radiation injury that can be used to triage thousands of individuals in a short time following a radiological or nuclear attack.

"The Homeland Security Council document, 'Planning Guidance for Response to a Nuclear Detonation' indicates that a 10-kiloton improvised nuclear device would likely be lethal to individuals within about a half-mile radius of the blast," says Chute.

"Outside this zone, however, thousands of individuals would be exposed to high-dose radiation but may be able to survive with prompt medical intervention. Further from the blast area, there would be additional thousands who have suffered little or no exposure, and may not need medical attention, but who will still be seeking it."

Chute says that such a scenario will require early and accurate triage of mass casualties to provide an effective health care response.

"Imagine a blast zone with a ring of triage stations at the perimeter. We believe that using our diagnostic assay in such points would allow us to screen tens of thousands of individuals in a 24-hour period and to distinguish true radiation victims from the uninjured," says Chute.

Chute says the assay will involve a single collection of only a few drops of blood that will be analyzed in a fully automated instrument with each result provided in about 30 minutes. That dramatically shortens the time it currently takes to analyze large numbers of genes, a process that takes several days and requires large equipment.

Researchers hope to have a prototype ready for demonstration by 2012.

Duke Scientists Map Brain Pathway For Vocal Learning

Wed, 13 Jan 2010 00:00:00 -0500

Scientists at Duke University Medical Center have identified neurons in the songbird brain that convey the auditory feedback needed to learn a song.

Their research lays the foundation for improving human speech, for example, in people whose auditory nerves are damaged and who must learn to speak without the benefit of hearing their own voices.

"This work is the first study to identify an auditory feedback pathway in the brain that is harnessed for learned vocal control,” said Richard Mooney, PhD, Duke professor of neurobiology and senior author of the study.

The researchers also devised an elegant way to carefully alter the activity of these neurons to prove that they interact with the motor networks that control singing.

The study, supported by an NIH grant, was published online in Neuron on Jan. 13.

Vocal learning isn’t a simple process. "One challenge the brain faces when trying to learn a new behavior is that it only receives feedback about performance tens or even hundreds of milliseconds after it has generated the motor commands controlling that performance," Mooney said.

"The challenge is pushed to an extreme if the brain has to use this sensory information in a retrospective way and still make corrections with millisecond precision, as humans and songbirds do when they learn to vocalize."

The problems that juvenile birds solve when they learn a song from a tutor bird are similar to the problems humans solve when we learn to speak, and birds and humans exploit similar neural systems to reach this solution, Mooney said.

The major question of this research was how the brain encodes and harnesses auditory feedback to shape the vocal performance in juvenile birds that are learning to sing.

In a painstaking experiment, lead author Huimeng Lei, PhD, used fine microelectrodes to locate neurons that become active in the pupil’s brain when it hears its own song, Mooney said. "This was a very difficult procedure that had to be exquisitely accurate. Huimeng was able to get the recordings working just right to locate the feedback-sensing neurons."

Once the scientists knew they had located the correct set of neurons, they passed a brief pulse of electricity through the implanted electrodes to alter neural activity associated with one of the notes that the pupil was learning to sing.

"We think that the stimulation alters what the pupil bird perceives, and it is this altered perception that results in the note becoming distorted (as it sings the song back)," Mooney said. "In contrast, if we stimulated directly in the motor network (which produces the note) we would trigger an immediate distortion of the targeted song syllable."

Because birds sing their song with millisecond precision, the scientists could determine how precisely the brain learned to assign perceived error to the part of the song where the stimulation occurred. "The acoustical features of the stimulated region of the song grew distorted over time," Mooney said.

Three findings of interest emerged. First, the distortion in the bird's singing was delayed and showed up anywhere from hours to weeks after the bird first heard the electrical noise pulse in its song.

Second, the distortion always came in the same place in the pupil bird’s song. This means the distortion was temporally precise and occurred at the exact point in the song where the electrical "noise" was introduced.

"The brain somehow is learning to associate the stimulation with a certain part of the performance, and then alter the performance accordingly," Mooney said.

Third, by disrupting neural activity at different stages of the learning process, they determined that the distortion effects were strongly age-dependent.

The target portion of the song degraded very quickly in the younger birds, sometimes within an hour. The older birds who experienced electrical interference kept singing properly for a while, but slowly their singing degraded, over a period of weeks.

"Because we are directly injecting an electrical pulse into the auditory feedback pathway, the changing ability of the brain to respond to the perceived error in performance likely reflects changes in the motor network itself," Mooney said.

Song precision is vital to songbirds because females select mates based in part on the temporal precision with which they sing. Temporal precision is also highly important in human speech, because acoustical features of two speech sounds may differ on the millisecond level.

This study lays the groundwork for scientists to improve human speech. For example, people whose auditory nerves are damaged may benefit as scientists explore how to stimulate auditory feedback pathways in the human brain that are important for speech learning. This is especially true for older children and adults who have been deaf and who need to learn speech well past the prime time for vocal learning, Mooney said.

This study also opens the door to exploring how the brain compares performance-related feedback to a sensory model, which is the basis of imitation, Mooney said.

"Imitation is the wellspring for much of human culture," he noted. "Because it would be impossible to use humans in experiments about initial vocal learning, songbird tutors and students provide a beautiful substitute system so that we can study the detailed brain mechanisms that underlie this relatively complex type of learning."

Duke Research Leads to “Extraordinary Measures” Film

Mon, 11 Jan 2010 00:00:00 -0500

When the film Extraordinary Measures debuts on January 22, it will tell the story of one man’s quest to obtain treatment for his children who suffer from a rare metabolic disorder called Pompe disease.

The real story began 20 years ago at Duke University Medical Center when pediatric geneticist Y.T. Chen, MD, PhD, began work on the first and only life-saving treatment for Pompe.

In 2006, the FDA approved the use of Myozyme, which is manufactured and marketed by Genzyme Corporation, based on Duke’s research. As a result, the children portrayed in the movie, and those who are living with Pompe worldwide, were treated with Myozyme and given their first fighting chance at life.

What Is Pompe Disease?

Pompe disease results when mutations occur in the gene that triggers the production of an enzyme called acid alpha-glucosidase (GAA). That enzyme is responsible for helping the body break down glycogen (sugar).

When it is absent or deficient the glycogen builds up in the body’s cells, damages tissues, and causes progressive heart and skeletal muscle weakness.

About one in 40,000 people have Pompe disease. In adults, the disease progresses slowly, and can result in reduced motor abilities and difficulty breathing.

It progresses more rapidly in the 30 to 35 infants born with Pompe in the U.S. annually, who would die in the first year of life without treatment. In infancy, the disease causes the heart muscle to enlarge and thicken, babies are weak and have difficulty breathing, explains Priya Kishnani, MD, a pediatric geneticist at Duke who is the world’s leading expert on Pompe.

"Myozyme is to Pompe disease what insulin is to diabetes," Kishnani explains.

"It does the job of the missing or malfunctioning enzyme. Given via four-hour intravenous infusions every two weeks for the rest of a patient’s life, Myozyme successfully improves heart and muscular function. With its use, children are able to meet their motor milestones, they are running, going to school and playing games.”

Journey from Bench to Bedside

Myozyme’s journey started in 1995 when Chen engineered a line of cells that could produce the GAA enzyme. Within one year, animal studies proved fruitful when birds missing the enzyme went from being unable to fly to flipping from their backs to their feet after several days of infusions. One of the birds even flew.

Kishnani was the lead investigator of the trials that would take Chen’s work out of the lab and into humans. Clinical trials started in 1999 with three frail babies.

Today, one of those babies is a healthy, 11-year-old boy who plays baseball and enjoys a normal life. "You couldn’t pick him out from a crowd," Kishnani says. But with only 11 years of experience, she cautions that it’s too early to predict the future.

"There are patients who have done remarkably well but others have not. We’ve learned that early initiation of treatment is paramount to a successful outcome."

It's the reason why Duke and others are pushing to include Pompe and other rare genetic diseases in the battery of newborn screening.

In Taiwan, where newborn screening includes Pompe, published studies reported a far superior outcome in babies who were identified with Pompe at birth."They are walking and have made marvelous motor gains," Kishnani says. The motor gains of children who were identified later "are not as robust."

What the Future Holds

Kishnani and her team continue to do research aimed at enhancing the longevity and quality of life for patients with Pompe.

One avenue is exploring strategies that will avoid the immune response that sometimes occurs when the body recognizes Myozyme as foreign. Another approach focuses on better muscle delivery of the enzyme therapy. The role of gene replacement therapy is also being explored as well as the significance of diet and exercise.

Duke researchers worked with others to develop a blood test to take the place of an invasive skin or muscle biopsy. “This simple drop of blood lets us diagnose patients in as quickly as 24 hours,” Kishnani says.

As the world is about to learn of a disease that has consumed her life, Kishnani sits back and smiles. "I never would have expected that a major Hollywood movie with stars like Brendan Fraser and Harrison Ford would focus on a topic so near and dear to my heart. The movie is a win-win for all of us in the field, but especially for the patients because the more awareness there is, the more likely they will be diagnosed early and treated."

Race, Obesity Affect Outcomes Among Diabetics Following Prostatectomy

Mon, 11 Jan 2010 00:00:00 -0500

Obese white men who have both diabetes and prostate cancer have significantly worse outcomes following radical prostatectomy than do men without diabetes who undergo the same procedure, according to research from Duke University Medical Center appearing in Cancer Epidemiology, Biomarkers & Prevention.

Many studies have shown that diabetes is associated with a lower risk of developing prostate cancer -- at least in white men -- but the effect of diabetes on outcomes after prostate cancer surgery has not been as clear.

"We found that diabetes was significantly associated with more aggressive disease in obese white men and less aggressive disease for all other subsets of men in our study," says Stephen Freedland, MD, associate professor of urology and pathology at the Duke Prostate Center at Duke University and member of the Urology Section, Veterans Affairs Medical Center in Durham.

Researchers have spent years assessing the interplay among race, weight, diabetes, and prostate cancer and have come up with mixed results.

Studies have shown that black men are significantly more likely than white men to develop prostate cancer, to have more aggressive disease, and to experience a greater likelihood of recurrence.

Diabetes is more prevalent among black adults than white adults (11.8 percent vs. 7.5 percent, respectively).

Studies show that obesity is also associated with increased risk of aggressive disease, recurrence, and death from prostate cancer -- and diabetes.

"Given that race and obesity are related to both aggressive prostate cancer and diabetes, we hypothesized that the association between diabetes and prostate cancer progression might vary by race and obesity," says Freedland.

The study, published in Cancer Epidemiology, Biomarkers & Prevention, examined the records of 1,262 men in the SEARCH database who underwent radical prostatectomy between 1988 and 2008. Researchers tracked the impact of diabetes upon tumor grade, the likelihood of recurrence and the amount of time it took for the patients’ PSA level to double (PSADT) after surgery, a measure of disease aggressiveness.

They found no link between diabetes and prostate cancer progression. But in a secondary analysis, after sorting the data by race and weight, investigators found an association between diabetes and an increased risk of recurrence and a trend toward more aggressive recurrence (reflected in a shorter doubling time of the PSA) -- but only among obese white men.

In all other subgroups, diabetes was associated with lower recurrence risk and longer PSADT.

"We really don’t know what mechanisms might be in place that could account for this relationship," says Freedland.

"But consider this: diabetes is associated with low levels of insulin and testosterone, an inhospitable environment for tumor growth. This is compounded in obese white men who also have lower insulin-like growth factor levels. The thinking is that if a tumor is powerful enough to grow in such a hostile environment, then it’s probably a pretty aggressive one."

Freedland says this is the first study to examine racial and body weight differences in the association between diabetes and prostate cancer progression, so these findings need to be validated before drawing firm conclusions regarding any relationships. Because all men in the study were healthy enough to undergo surgery also means that the results may not be applicable to a general population.

The study was supported by grants from the Department of Veterans Affairs, the Department of Defense Prostate Cancer Research Program, the NIH, the Georgia Cancer Coalition, and the American Urological Association Foundation/Astellas Rising Star in Urology Award.

Jayakrishnan Jayachandran, MD, (deceased), is the lead author of the study. Additional colleagues who contributed to the research include William Aronson, from the Urology Section, Veterans Affairs Greater Los Angeles Health System; Martha Terris, from the Urology Section, Veterans Affairs Medical Center and the Medical College of Georgia; Joseph Presti, Jr., of the Veterans Affairs Medical Center Palo Alto and Stanford University; Christopher Amling, Oregon Health & Science University; and Christopher Kane, University of California San Diego.

H1N1 Vaccination Walk-In Clinics in Durham

Thu, 07 Jan 2010 00:00:00 -0500

Durham County Health Department and Duke University Medical Center, in collaboration with Durham Public Schools, are offering walk-in H1N1 vaccinations for all people six months of age and older.

The walk-in clinics will be held on Saturday, January 9, 2010, from 10 a.m. to 3 p.m. at these locations:

Hillside High School, 3727 Fayetteville Street, Durham, NC 27707
Riverside High School, 3218 Rose of Sharon Road, Durham, NC 27712
Neal Middle School, 201 Baptist Road, Durham, NC 27704

No appointments are needed.

The health department provides H1N1 vaccinations at no charge.

For more information, call 919-560-7882 or visit durhamcountync.gov/flu.

H1N1 vaccination is the best protection from H1N1 flu.

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