University Times

Vitamin D fights mold allergy

Vitamin D may be an effective therapy to treat and even prevent allergy to a common airborne mold that can cause severe complications for patients with cystic fibrosis and asthma, according to researchers from Pitt’s School of Medicine, Children’s Hospital and Louisiana State University.

Results of the study, led by Jay Kolls, Pitt professor of pediatrics and immunology and Children’s Hospital lung disease researcher, were published in the September issue of the Journal of Clinical Investigation.

Aspergillus fumigatus does not cause illness in the vast majority of those who inhale it, but the mold can cause life-threatening allergic symptoms in patients with cystic fibrosis. Up to 15 percent of patients with cystic fibrosis will develop a severe allergic response, known as allergic bronchopulmonary aspergillosis (ABPA). Some patients with asthma also can develop ABPA.

The researchers studied cystic fibrosis patients at Children’s Hospital who had A. fumigatus infections. The researchers found that those who developed ABPA had a heightened response by immune cells known as type 2 T helper (Th2) cells, and that a protein known as OX40L was critical to this heightened response. The heightened Th2 response correlated with lower levels of vitamin D as compared with the non-ABPA patients. Adding vitamin D to these cells in the laboratory substantially reduced the expression of OX40L and increased the expression of other proteins critical to the development of allergen tolerance.

“We found that adding vitamin D substantially reduced the production of the protein driving the allergic response and also increased production of the protein that promotes tolerance,” said Kolls, who also is chair of genetics at LSU Health Sciences Center, New Orleans.

“Based on our results, we have strong rationale for a clinical trial of vitamin D to determine whether it can prevent or treat ABPA in patients with cystic fibrosis.”

Cystic fibrosis is an inherited chronic disease that affects the lungs and digestive system. A defective gene and its protein product cause the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections and obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

Researcher wins award from Hyundai

Pediatric oncologist and Children’s Hospital cancer researcher J. Anthony Graves was named a 2010 Hyundai Scholar and awarded $85,000 to support his research as part of the automaker’s Hope on Wheels program.

Graves studies the c-Myc oncogene’s role in tumor formation.

The c-Myc gene product is overproduced in many cancers, including breast and colon cancers, and in leukemias and lymphomas. High cellular levels of c-Myc generate genomic instability, which is thought to be essential in the development of a tumor. One way c-Myc can cause genomic instability is by the production of free radicals and reactive oxygen species (ROS), which can damage cells.

Graves is studying c-Myc mutants that have lost the ability to generate ROS in comparison with those that retain the capability.

“It is my hypothesis that mutations that result in higher levels of cellular ROS will be more capable of causing cancer than those that do not. If this hypothesis is supported then it will lead to a far greater understanding of the mechanism by which c-Myc can cause a tumor in vivo,” he stated.

Graves also is studying the interaction of c-Myc with a family of proteins called peroxiredoxins (Prx’s), which help cells protect themselves from ROS damage. The most abundant member of the family (Prx1) has been shown to interact physically with c-Myc and modulate its function, decreasing its ability to transform cells.

UCSUR: Local O&G leases booming

Researchers in the University Center for Social and Urban Research (UCSUR) have found that 7 percent of Allegheny County’s land has been leased for oil and gas exploration and extraction since 2003.

In addition, the number of properties in the county leased for oil and gas exploration increased by 322 percent between 2008 and 2009.

An interactive map of the 2,000-plus parcels leased for oil and gas exploration between 2003 and May 2010 is available on UCSUR’s Pittsburgh Urban Blog. The PUB (www.ucsur.pitt.edu/thepub.php) makes research on regional statistics and trends readily available.

Sabina Deitrick, co-director of UCSUR’s urban analysis program, said the oil and gas leases reveal a rapidly expanding pursuit of drilling and exploration rights in the county. New oil and gas leases taken out by parcel increased steadily from 29 in 2003 to 217 in 2008 and rocketed to 1,102 in 2009.

The database shows Dale Property Services/DPS Penn holds a lease on 1,654 parcels  — nearly half of all properties leased for oil and gas since 2003 in the county, while Monroeville-based Huntley and Huntley has the most land area under lease with 10,990 of the 35,393 acres leased in the county since 2003.

Symptoms unreliable indicator of Crohn’s

The Crohn’s Disease Activity Index (CDAI), which relies on patient symptoms to determine whether or not Crohn’s disease is active, may not reliably indicate whether a patient’s disease has returned after corrective surgery, according to a study published in Inflammatory Bowel Diseases.

“The natural course of Crohn’s disease often is symptom-free,” said Miguel Regueiro, co-director of the Inflammatory Bowel Disease Center and Department of Medicine faculty member. “The disease can present silently. In fact, many patients with Crohn’s may have had the disease for years without having symptoms. Similarly, after surgery, most patients feel quite well for many years. We have found that most patients with recurrent Crohn’s disease after surgery also do not have symptoms.

“This is a concern because many patients with post-surgical Crohn’s disease recurrence will ultimately need another surgery and if they cannot feel their disease, adequate treatment may not be started. Because of  this, we need to look for objective evidence of the disease instead of relying on patients to report how they feel.”

Twenty-four patients with Crohn’s disease were studied to discover whether disease recurrence detected by endoscopy agreed with patient symptom reports. According to the results, half of the patients went into remission after surgery while the other half did not, and there was little or no relationship between the return of the disease and the symptoms patients reported.

“Because patient symptoms don’t indicate whether Crohn’s disease has returned, we need to change how we consider symptom-based care and begin utilizing objective evidence, such as endoscopy, to understand the course the disease takes in individual patients. This way, we can detect the disease early, begin the correct treatment and potentially prevent future complications and the need for more surgery,” said Regueiro.

Medicare coverage increases antibiotic use

A study by Graduate School of Public Health researchers found that improved drug coverage under Medicare Part D has led to an increase in senior citizens’ use of antibiotics. The study, published in the Aug. 23 issue of Archives of Internal Medicine, suggests recent changes in drug coverage improved the use of antibiotics for pneumonia, but could lead to unnecessary spending on expensive broad-spectrum antibiotics and the overuse of inappropriate antibiotics.

The study included more than 35,000 Medicare beneficiaries and compared their use of antibiotics two years before and after the implementation of Medicare Part D, which reduced out-of-pocket drug spending between 13 and 23 percent. They found that antibiotic use increased most among beneficiaries who lacked drug coverage prior to enrolling in Medicare Part D.

Beneficiaries who previously had limited drug coverage also were more likely to fill prescriptions for antibiotics after enrolling in Part D. The largest increases were found in the use of broad-spectrum, newer and more expensive antibiotics.

Researchers also noted that the use of antibiotic treatment for pneumonia tripled among those who previously lacked drug coverage, which they say is encouraging given the high mortality associated with community-acquired pneumonia among the elderly. However, they also found increases in antibiotic use for other acute respiratory tract infections (sinusitis, pharyngitis, bronchitis and non-specific upper respiratory tract infection) for which antibiotics generally are not indicated.

“Overuse of antibiotics is a common and important problem that can lead to medical complications and drug resistance,” said the study’s lead author, Yuting Zhang, a faculty member in health economics.

“When drug coverage is generous, people are more likely to request and fill prescriptions for antibiotics, which may lead to misuse,” said Zhang. “Although many interventions have helped curb antibiotic prescribing for acute respiratory tract infections and other conditions, our study indicates there may still be substantial room for improvement through education and changes in reimbursement practices to reduce inappropriate use of these drugs.”

Pitt co-authors include Bruce Y. Lee of the Department of Medicine and Julie M. Donohue of health policy and management.

Breastfeeding cuts moms’ diabetes risk

Mothers who did not breastfeed their children have significantly higher rates of type 2 diabetes later in life than moms who breastfed, report Pitt researchers in a study published in the September issue of the American Journal of Medicine.

“We have seen dramatic increases in the prevalence of type 2 diabetes over the last century,” said Eleanor Bimla Schwarz, a faculty member in medicine, epidemiology and obstetrics, gynecology and reproductive sciences. “Diet and exercise are widely known to impact the risk of type 2 diabetes, but few people realize that breastfeeding also reduces mothers’ risk of developing the disease later in life by decreasing maternal belly fat.”

The study included 2,233 women ages 40-78. Overall, 56 percent of mothers reported they had breastfed an infant for at least one month. Twenty-seven percent of mothers who did not breastfeed developed type 2 diabetes and were almost twice as likely to develop the disease as women who had breastfed or never given birth. In contrast, mothers who breastfed all of their children were no more likely to develop diabetes than women who never gave birth. These long-term differences were notable even after considering age, race, physical activity and tobacco and alcohol use.

“Our study provides another good reason to encourage women to breastfeed their infants, at least for the infant’s first month of life,” said Schwarz. “Clinicians need to consider women’s pregnancy and lactation history when advising women about their risk for developing type 2 diabetes.”

Candace K. McClure of epidemiology was among the study co-authors.

Humans can copy RNA as well as DNA

Single-molecule sequencing technology has detected and quantified novel small RNAs in human cells that represent entirely new classes of the gene-translating molecules, confirming a hypothesis that mammalian cells are capable of synthesizing RNA by copying RNA molecules directly. Researchers from the School of Medicine, Helicos Biosciences Corp., Integromics and the University of Geneva Medical School recently reported the findings in the journal Nature.

Co-author Bino John, a faculty member in the School of Medicine’s Department of Computational and Systems Biology, said, “For the first time, we have evidence to support the hypothesis that human cells have the widespread ability to copy RNA as well as DNA. These findings emphasize the complexity of human RNA populations and suggest the important role for single-molecule sequencing for accurate and comprehensive genetic profiling.”

Scientists had thought that all RNA in human cells was copied from the DNA template, John explained. The presence of mechanisms that copy RNA into RNA, typically associated with an enzyme called RNA-dependent RNA polymerase, only has been documented in plants and simple organisms, such as yeast, and implicated in regulation of crucial cellular processes.

Since thousands of such RNAs have been detected in human cells and because these RNAs have never before been studied, further research could open up new fronts in therapeutics, particularly diagnostics, John said.

In the study, the researchers profiled small RNAs from human cells and tissues, uncovering several new classes of RNAs, including antisense termini-associated short RNAs, which likely are derived from messenger RNAs of protein-coding genes by yet uncharacterized, pervasive RNA-copying mechanisms in human cancer cell lines.

Patrice Milos, chief scientific officer at Helicos Biosciences, said, “This class of non-coding RNA molecules has been historically overlooked because available sequencing platforms often are unable to provide accurate detection and quantification.

“Our technology provides the platform capability to identify and quantify these RNAs and reinforces the potential clinical advantages of our single molecule-sequencing platform.”

Co-authors included A. Paula Monaghan of neurobiology and Sangwoo Kim of computational biology.

New math solution described

Pitt-Bradford mathematics professor Yong-Zhuo Chen has described a new method to solve a type of difference equation. His paper, “Some Contractive Type Mappings and Their Application to Difference Equations,” was presented recently at the American Mathematical Society’s eastern sectional meeting and has been accepted for publication in the Journal of Difference Equations and Applications.

Difference equations are used to model phenomena in biology, ecology, physiology, physics, engineering and economics.

Chen is chair of UPB’s Division of Physical and Computational Sciences.

Head and neck cancer research funded

Researchers at the School of Medicine and the University of Pittsburgh Cancer Institute (UPCI) have been awarded an $800,000 federal grant to develop agents to inhibit a cellular signaling protein that plays a key role in triggering and supporting the growth of many cancers, including cancers of the head and neck.

A member of a protein class called Signal Transducers and Activators of Transcription (STAT3), activated in excess levels, can drive the transformation of healthy cells into cancer, said principal investigator Jennifer R. Grandis, professor of otolaryngology and pharmacology and director of the UPCI head and neck program. The abnormality has been found not only in head and neck cancers, but also in many malignancies including breast, prostate and lung cancer.

“This protein can send signals to other molecules encouraging the replication and spread of cancer cells, promoting new blood vessel growth to tumors and suppressing the immune response against the disease,” Grandis explained. “Animal studies have shown that inhibiting it can shrink tumors and prolong survival, so it represents an important target for therapies against a range of cancer types.”

With funding from the National Cancer Institute, Grandis and her team will identify and develop small-molecule inhibitors of STAT3 activation, which is present in squamous cell carcinoma of the head and neck (SCCHN) and in 95 percent of all head and neck cancers. The best candidates will be tested in animal models of SCCHN.

Current treatments for SCCHN include surgery and chemoradiation, and the only approved molecular approach is the monoclonal antibody cetuximab, which inhibits epidermal growth factor receptor (EGFR).

“Although EGFR expression is common in these tumors, cetuximab works only in a subset of patients, leaving the rest likely to succumb to their cancers,” Grandis noted. “It’s possible that STAT3 activation is contributing to resistance to the drug, so blocking it could make cetuximab treatment more effective.”

Co-principal investigators include John Lazo and Paul A. Johnston, both of the Department of Pharmacology and Chemical Biology.

Corneal stem cell research funded

The Louis J. Fox Center for Vision Restoration, a joint program of UPMC Eye Center and Pitt’s McGowan Institute for Regenerative Medicine, recently received a $244,000 donation from the Western Pennsylvania Medical Eye Bank Foundation.

The donation, to be matched by UPMC, will be used to further the School of Medicine’s research on stem cell therapy for corneal scarring.

James L. Funderburgh, senior investigator and professor in the Department of Ophthalmology, said, “Our preclinical studies support the idea that stem cell therapy can provide sight to a large number of individuals with corneal blindness. The timing of this generous donation provides an extraordinary opportunity for us to advance this research from the lab to the clinic.”

Through experiments conducted in mice, Funderburgh and his team have found that stem cells collected from the stromal layer of human corneas restore transparency without triggering a rejection response when injected into eyes that are scarred and hazy. Their study was published in the April 2009 edition of the journal Stem Cell.

With the new funding, the Pitt research team will develop standard procedures for preparing the stem cells so that they can be used in human studies, after first verifying their safety in animal models.

The Fox Center’s main focus is discovery and development of new cures for blindness and visual impairment, especially for those with problems affecting the retina, optic nerve, cornea and lens. Through basic and clinical research, it will provide vision restoration through the augmentation of existing visual pathways or by providing vision through non-visual means.

Stimulus funds buy cyclotron

Radiology professor Chet Mathis, director of UPMC’s PET facility, received a $2.7 million high-end instrumentation grant from the National Institutes of Health to purchase a new cyclotron for UPMC Presbyterian. The NIH equipment funds are derived from American Recovery and Reinvestment Act funds specifically designated for new research equipment.

D’Urso receives DARPA grant

Brian D’Urso’s proposal “Quantum Interactions of a Graphene Nanomechanical Oscillator With a Single Spin” recently was selected for a Defense Advanced Research Projects Agency  (DARPA) Young Faculty Award.

D’Urso, a faculty member in the Department of Physics and Astronomy, is among 33 researchers at 24 universities chosen in this year’s YFA class. The program focuses on untenured faculty, emphasizing those without prior DARPA funding.

The award program aims to identify and engage rising research stars in junior faculty positions at U.S. academic institutions and expose them to Department of Defense (DoD) needs and DARPA’s program development process.

The YFA program provides funding, mentoring and industry/DoD contacts to these faculty early in their careers to develop their research ideas in the context of DoD needs. The program’s long-term goal is to develop the next generation of academic scientists, engineers and mathematicians in key disciplines who will focus a significant portion of their career on DoD and national security issues.

Selected researchers receive grants of approximately $300,000 to develop and validate their research ideas over a period of two years. YFA recipients also participate in military base visits or exercises that provide them with first-hand perspectives of current issues faced by DoD war fighters.

Seniors’ fall prevention study funded

A $1.5 million grant from the Centers for Disease Control and Prevention to the Graduate School of Public Health (GSPH) will explore the effectiveness of programs to prevent falls in seniors, which occur in more than one-third of adults 65 and older every year in the United States.

Led by principal investigator Steven M. Albert, faculty member in behavioral and community health sciences at GSPH, in collaboration with the Pennsylvania Department of Aging, the two-year grant will compare two interventions:  Healthy Steps for Older Adults, an education-only program, and Healthy Steps in Motion, an education-plus-exercise program. Participants will be assigned randomly to the programs.

“Falls are the leading cause of death from injury among older adults, and yet we know little about how prevention programs work in the real world,” said Albert. “This study will give us needed guidance on how we can prevent such falls, which result in billions of dollars in health care costs.”

The study will enroll 750 seniors in each arm of the trial as well as 300 Latino seniors, who represent an aging U.S. population. Lay service providers will be trained to identify people at risk of falling and make referrals for home safety assessments.

The study was funded through the CDC’s prevention research program under the 2009 Recovery Act for comparative effectiveness research.

Beta cells replicated

School of Medicine researchers have found a single stimulatory molecule can induce human insulin-producing beta cells to replicate for at least four weeks in a mouse model of diabetes. Their work appeared in Diabetes, a journal of the American Diabetes Association.

They also found several cocktails of molecules that drive human beta cells to replicate, as well as important differences between mouse and human beta cells that could influence how these approaches are best used to treat diabetes.

Senior author Andrew F. Stewart, a faculty member in medicine and chief of the Division of Endocrinology and Metabolism, said: “Our team was the first to show that adult human beta cells can be induced to proliferate or grow at substantial rates, which no one thought possible before. Now our effort has been to unravel these regulatory pathways to find the most effective strategy that will allow us to treat — and perhaps cure — diabetes by making new insulin-producing cells.”

Endocrinology faculty member and study lead author Nathalie M. Fiaschi-Taesch and the team discovered that combining elevated amounts of the regulatory molecules cdk4 or cdk6 with a variety of D-cyclin proteins, particularly cyclin D3, stimulates human beta cell replication in test tubes.

Cyclin D2 is present in and essential for rodent beta cell replication and function, but the team showed that molecule is barely detectable in human cells, and beta cell replication could be sustained for at least four weeks in a model in which mice were transplanted with human beta cells engineered to overproduce cdk6.

Blood sugar normalized in the diabetic mice transplanted with small numbers of human beta cells, indicating that the cells functioned properly to produce needed insulin.

Mice don’t appear to make cdk6 naturally, but they do have cdk4 and cyclins D1 and D2, so standard rodent studies of beta replication might have led scientists to pursue the wrong molecules in their quest to stimulate human beta cell replication, Stewart noted.

He and his colleagues continue to explore many other regulatory proteins that could play a role in encouraging or thwarting beta cell replication.

Other Pitt authors of the paper included Fatimah Salim, Jeffrey Kleinberger, Ronnie Troxell, Karen Selk, Edward Cherok, Karen K. Takane and Donald K. Scott, all of the Department of Medicine’s Division of Endocrinology and Metabolism.

The research was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the Juvenile Diabetes Research Foundation, the Spanish Ministry of Science and Innovation, and the Pam and Scott Kroh and the Don and Arleen Wagner family foundations.

DoD funds semiconductor research

Physics professor Jeremy Levy is among the 32 recipients sharing a total of $227 million in Department of Defense (DoD) research awards over five years.

Levy’s five-year, $7.5 million grant is for a superconducting semiconductor project, “Quantum Preservation, Simulation & Transfer in Oxide Nanostructures,” to be undertaken in conjunction with researchers at the University of California-Santa Barbara, the University of Wisconsin-Madison, Cornell and Michigan State.

Levy will lead the team in combining the properties of semiconductors such as those used to make computer processors and superconductors, which allow for the perfect flow of electricity, into a single material suitable for the development of quantum computers.

The team will use these superconducting semiconductors to develop new types of quantum memory, perform quantum simulation and create new methods for transferring quantum information from one medium to another.

These functions are essential to realizing quantum computers, which are yet to exist in any practical form and require a precise control of the laws of quantum physics that has so far been difficult to achieve, Levy explained.

The awards are the result of the fiscal 2010 competition conducted by the Army Research Office, the Office of Naval Research and the Air Force Office of Scientific Research under the DoD multidisciplinary university research initiative program.

According to the DoD, based on the proposals selected in fiscal 2010, a total of 67 academic institutions are expected to participate in the 32 research efforts.

Lack of infant routine predicts later anxiety

Infants with irregular patterns of sleeping, eating and playing were significantly more likely to experience symptoms of anxiety more than a decade later, according to a study led by School of Medicine researchers in collaboration with researchers at the University of Wisconsin School of Medicine and Public Health.

Their findings were published recently in Psychiatry Research.

Certain psychiatric symptoms, particularly related to depression and anxiety, are associated with dysfunction of the 24-hour biological clock, also known as the circadian system.

In this study, the research teams followed 59 children for 13 years, starting at one month of age, to determine if the regularity of their daily behaviors in infancy could predict depression and anxiety symptoms when the children were older.

To measure lifestyle routines and sleep regularity in babies, the researchers created a diary tool that parents used to document very young babies’ routines a week at a time. In 1990 and 1991, 59 couples tracked their one-month-old babies for two weeks, recording sleep times as well as feeding, playing, diaper changing and receiving comfort.

Psychiatry professor Timothy H. Monk, lead co-author of the study and director of the human chronobiology research program at the School of Medicine, said: “We found that a baby’s daily routine and sleep patterns at one month were predictive of the amount of anxiety shown more than 10 years later while the child was attending school, but we did not find a significant correlation with depression.

“For many years, experts have believed that regularity in an individual’s daily lifestyle might be associated with better mental health,” noted Monk. “By being able to follow these children from birth to the 9th grade, we can show that greater regularity, even in very early life, can be associated with less school-age anxiety later on.”

The researchers suggest that greater regularity in daily activities may increase the predictability of an infant’s demands, leading to enhanced parental perception of the baby’s cues and increased parental confidence in meeting the infant’s needs. They argue that more confident and perceptive parenting, in turn, supports the development of an infant’s emotional regulatory capacities. The ability to self-soothe and self-regulate is an important emotional regulatory skill.

Co-author Linnea R. Burk of the University of Wisconsin stated, “Further, cognitive skills, such as directed-attention, or the ability to concentrate, also are likely involved in emotion regulation. These attention-directed processes may help to adjust emotional arousal and aid children in managing overt behavior when emotions are less well regulated by other means.

“Children with a well-developed ability to direct attention in a variety of situations likely use less cognitive effort, and therefore may have more cognitive resources available to aid in regulatory processes.”

The study supports the potential importance of the circadian system and its development in the life of the child, and possibly suggests a genetic basis that the researchers will explore in future work.

David J. Kupfer, Thomas Detre professor of psychiatry and professor of neuroscience and clinical and translational science, was among the study co-authors.

NSF aids PSC computing system purchase

The National Science Foundation (NSF) has granted $2.8 million toward the Pittsburgh Supercomputing Center (PSC)’s acquisition of a scalable, shared-memory computing system and associated disks. The SGI Altix UV system features extremely large, coherent shared-memory and opens a new computational capability for U.S. scientists and engineers.

The Altix UV system will have 4,096 cores, in 512 eight-core Intel Xeon (Nehalem) processors, with 32 terabytes of memory, organized as two connected 16-terabyte coherent shared-memory systems — making these the largest coherent shared-memory systems in the world.

Coherence, a feature related to the synchrony of read-write operations by different processors within the system, is an important feature in many large data-analysis tasks.

PSC will integrate the new system into the TeraGrid, the NSF program of comprehensive cyber-infrastructure, greatly increasing the capability available for U.S. science and engineering research.

In a joint statement, PSC scientific directors Michael Levine, of Carnegie Mellon and Ralph Roskies of Pitt said: “Because of the extraordinary memory size and relative ease of programming made possible by the Altix UV shared-memory structure, scientists and engineers will be able to solve problems that were heretofore intractable. For many research communities — including data analysis and many areas of computer science — it will open the door to use of high-performance computation and thereby expand the abilities of scientists to ask and answer questions.”

In computer terms, “shared memory” means that a system’s memory can be accessed directly from all of its processors, as opposed to distributed memory (in which each processor’s memory is accessed directly only by that processor). Because all processors share a single view of data, a shared memory system is relatively easy to program and use.

Because of its shared-memory design, the new PSC system will complement other NSF systems, most of which are based on distributed-memory architectures.

The 4,096 processor cores and 32 terabytes of shared memory are interconnected using SGI’s next-generation high-bandwidth, low-latency NUMAlink 5 interconnect. This interconnect has specialized features that enable scalable shared-memory or message-passing applications to run with higher levels of parallel efficiency so that researchers can assign more processor cores simultaneously to the same task. This allows researchers to address larger problems and solve them more quickly.

Production use of the system will begin in TeraGrid’s October 2010 allocation cycle.

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