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November 20, 2003

Research Notes

Grants awarded to researchers

The chemistry department’s Sanford Asher has received a $301,204 grant from the National Institute of General Medical Sciences to continue developing UV resonance raman spectroscopy to examine protein structure and dynamics.

The U.S. Department of Education has granted $268,149 to Robert Hayden for programmatic support of Pitt’s Center for Russian and East European Studies.

The U.S. Office of Rural Health Policy has awarded $838,647 to Michael Meit of Pitt’s Bradford campus to assess Pennsylvania’s rural health care and public health workforce needs and academic programs to address those needs.

Mascaro Construction has awarded $319,307 to Julie Vandenbossche of civil and environmental engineering for instrumentation and early-age evaluation of U.S. Route 22.


Pitt part of initiative to improve outcomes in older people with cancer

The University of Pittsburgh Cancer Institute (UPCI), in collaboration with the division of geriatrics and gerontology and the Institute on Aging at Pitt’s School of Medicine, has received a grant from the National Cancer Institute (NCI) and the National Institute on Aging to understand the biology of the effects of aging on the cancer process and to improve health outcomes in older people with cancer.

The grant, to be awarded in the amount of $650,000 per year, is part of a five-year, $25-million initiative announced by the NCI to accelerate research into the relationship between aging and cancer. Pitt is one of eight academic centers in the country selected to be part of the new initiative.

“People at ages 65 and older are at the highest risk for cancer and tend to be the most neglected when it comes to cancer care,” said Ronald Herberman, principal investigator of the project and director of UPCI.

According to NCI, the need for research on cancer and aging has never been more urgent as the number of individuals ages 65 and older is expected to jump from 23 million in 2003 to 70 million by 2030. People who are 65 years of age and older have a cancer incidence rate 10 times greater than the rate for younger people and a mortality rate 16 times greater. This issue is of particular relevance in Allegheny County and western Pennsylvania, where the proportion of elderly residents is especially high.

“One of our major goals for this award is to better understand the needs and concerns of older adults with cancer,” said Stephanie Studenski, a Pitt professor of geriatrics and co-principal investigator of the project.

The project at Pitt will focus on clinical trials to test treatment efficacy and tolerance in older cancer patients, behavioral and social issues faced by the elderly and the biology of aging.


Professor reveals fundamental physical behavior of silicon

Experiments by Pitt professor Hrvoje Petek have revealed how electrons at the instant of their generation interact with the atoms in solid crystalline silicon to form quasiparticles.

Petek and co-authors Muneaki Hase and Masahiro Kitajima of the National Institute of Materials Science reported their findings in the Nov. 6 issue of Nature.

Virtually all electronic devices rely on silicon. Complex electronic components such as microprocessors are built of basic silicon switching elements — transistors.

“We have made a significant step in understanding the fundamental properties of silicon that I hope, over the next few decades, will substantially impact the development of future electronic devices,” said Petek, professor of physics and chemistry in the Department of Physics and Astronomy.

Using an ultrafast laser that generates flashes of light 10 femtoseconds — 10 quadrillionths of a second — in duration, Petek and his co-investigators could induce the formation of quasiparticles and quantify their properties from the changes in the optical properties of excited silicon.

Quasiparticles refer to charges that carry electrical current, or electrons, and vibrations of atoms, or phonons, that cause electrical resistance in semiconductor devices. According to the laws of quantum mechanics, a yin-yang relationship exists between electrons and phonons — the decay of one generates the other, and vice versa.

Understanding how quasiparticles form and decay reveals the quantum mechanical principles that underlie how electronic transistors operate. Once it is understood how silicon behaves in the quantum mechanical regime, it may be possible to devise semiconductor chips that are more than a thousand times faster than current chips.

Quasiparticle buildup has been observed in other semiconductors, but not in silicon, because it has unfavorable properties for optical experiments with what physicists call ultrafast lasers. The success of Petek’s group was made possible by the unique laser and optical measurement system developed in his laboratory.

“We have been able to capture, for the first time, how electrons in silicon evolve under quantum mechanical principles,” said Petek.

Quasiparticles are rarely expressed in present-day devices because, at their current size and speed, classical physics is adequate to explain how they function. However, in the next few decades, transistor size will shrink and switching time will speed up to the point where only quantum mechanical laws will describe electronic device operation. This could present a revolution in technology.


Protein biomarkers diagnose ALS accurately, quickly

Detection of protein abnormalities in cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS) may allow physicians to more rapidly diagnose and better monitor drug efficacy in clinical trials for the disease, according to a study presented by a Pitt researcher Nov. 17.

These findings may lead to the first test for early-stage ALS, also know as Lou Gehrig’s disease.

The study, presented by Robert Bowser of Pitt’s School of Medicine at the annual meeting of the International Alliance of ALS/MND Associations and International Symposium on ALS/MND, identified ALS-specific biomarkers by protein profiling of cerebrospinal fluid from 25 ALS patients and 35 control subjects.

“There are no known diagnostic biomarkers for ALS and no sensitive methods to determine whether a particular drug is working in an ALS patient, nor any way to best test drug combinations for effectiveness,” said Bowser, who is associate professor of pathology and director of the ALS Tissue Bank at Pitt. “A panel of biomarkers would not only be useful in a more rapid diagnosis of ALS, but also would be a valuable tool to evaluate drug efficacy in clinical trials.”

CSF samples were obtained from recently diagnosed ALS patients and control subjects who did not have ALS.

Using mass spectrometry to characterize protein peaks that exhibit statistically significant alterations between ALS patients and the control groups, Bowser and his colleagues identified protein biomarkers that diagnose ALS with near 100 percent specificity and sensitivity.

Bowser’s research is in collaboration with investigators at Massachusetts General Hospital/ Harvard.

ALS is a fatal neurodegenerative disease that attacks nerve cells and pathways in the brain and spinal cord. When cells die, voluntary muscle control and movement are lost. Those patients in the later stages of the disease are totally paralyzed even though their minds remain alert. The average life expectancy of a person with ALS is between two to five years from time of diagnosis.


Simple tests could signal, prevent heart disease in women

A few safe and simple tests could identify and possibly prevent coronary heart disease in middle-aged women, according to findings reported by a Pitt researcher at the American Heart Association’s scientific sessions Nov. 9-12.

“Most women gain one to two pounds per year as they approach and go through menopause, and a percentage of them will go on to develop heart disease as a result,” said Lewis H. Kuller, professor of epidemiology at Pitt’s Graduate School of Public Health. “Keeping one’s waist circumference from expanding is a good way to avoid a negative outcome, but more targeted monitoring of other predictors, such as insulin, adiponectin and coronary calcium, can give a more accurate indication of when a woman is entering the danger zone.”

Unlike the fat that accumulates at other points on the body, waistline fat surrounds the abdominal organs, setting off physiological changes that can lead to a variety of diseases and disabilities.

A percentage of women who gain waistline fat at middle age develop high levels of insulin, or insulin resistance, throwing off their bodies’ delicate glucose metabolism and triggering in some the development of smaller and numerous low-density lipoprotein (LDL) particles, which can lead to the development of coronary calcium deposits. These deposits indicate risk of heart attack.

Kuller and his colleagues have found that monitoring a woman’s condition through a few simple tests can signal when action should be taken to stop the cascade of events that could otherwise lead to heart attack. Insulin resistance can be measured by testing blood levels of insulin, glucose and adiponectin — a type of fat-storing cell. Lipoprotein particles can be measured from a blood sample as well, and coronary calcium deposits can be discovered via electron beam tomography, a quick and non-invasive scan. If tests show any red flags, therapeutic interventions can be initiated immediately.


“There are very effective therapies, both pharmacological and nonpharmacological, to prevent the progression of insulin resistance, the development of small and numerous LDL particles and, potentially, the progression of atherosclerosis,” said Kuller. These interventions are now being tested in Pittsburgh as part of the Woman On the Move through Activity and Nutrition (WOMAN) study, which Kuller is leading.


Sex-specific gene found for depression

Researchers at Pitt have identified variants of a gene that if inherited by women may contribute to the development of depression. The same variants do not impact men, the researchers say.

The finding, published in the current issue of the journal Molecular Psychiatry, is the first time scientists have been able to zero in on a specific susceptibility gene for depression.

Depression is the second-leading cause of disability worldwide, affecting nearly 10 percent of the population. According to George S. Zubenko, professor of psychiatry at Pitt’s School of Medicine and adjunct professor of biology at Carnegie Mellon University, women are twice as likely as men to develop depression, and genetic differences appear to account for some of that disparity.

These latest results build on research published by Zubenko and his team in October 2002 that identified a small region of chromosome 2 — equal to 0.01 percent of the human genome — as the potential hiding place for a susceptibility gene for depression in women.

“These findings confirm our earlier research suggesting the existence of susceptibility genes that have sex-limited effects on the vulnerability of women to developing severe depression,” said Zubenko. “More than 80 percent of women in our study who inherited a particular variant of CREB1 developed depressive disorders, while a second version of this gene appeared to have protective effects.”

CREB1 is a gene that encodes a regulatory protein called CREB that orchestrates the expression of large numbers of other genes that play important roles in the brain and the rest of the body as well. The widespread importance of CREB as a genetic regulator throughout the body suggests that the newly identified CREB1 variants may influence the development of additional psychiatric disorders related to depression, such as alcohol and other substance use disorders, as well as medical conditions that are associated with depression.

The identification of CREB1 leads Zubenko’s team to believe that genes for other components of cell-signaling pathways that operate through CREB may be involved in mood disorders.

Alterations in CREB1 expression have been reported in the brains of patients who died with major depression, those of animal models of major depression and related disorders, and in the brains of animals treated with antidepressant drugs. CREB also has been implicated in neuronal plasticity, cognition and long-term memory, abnormalities of which commonly occur in patients with major depression, that may predispose patients to the onset or recurrence of major depression, and may be related to the eventual development of irreversible dementias like Alzheimer’s disease in some patients. Interactions of CREB with estrogen receptors might explain how inherited variants of CREB1 could affect the susceptibility of major depression only in women.

According to Zubenko, further progress in diagnosis and treatment of clinical depression that result from these findings will likely take some time, but research such as this will likely change the way doctors diagnose and treat major depression.

The study received funding from the National Institute of Mental Health.


Caregivers for dementia patients need more support

Findings from the first major study to follow family members who provide care to an elderly loved one with dementia show the vast majority of caregivers need more support before the death of their loved one.

The results appeared Nov. 12 in the New England Journal of Medicine.

According to lead author Richard Schulz, professor of psychiatry at Pitt’s School of Medicine, family caregivers of patients with end-of-life dementia endure a protracted and stressful period of caregiving prior to death, but after death express considerable relief and remarkable emotional resiliency.

Schulz said: “It is possible that caregivers who know their loved one is on a trajectory towards death grieve for that person before death.”

At the same time, the  research showed that after the death, caregivers had clinically lower depression within three months and significant declines in depression after a year.

Schulz and his colleagues followed 217 family caregivers of persons with dementia during the year before the patient’s death, then continued to follow them for a year afterwards.

Half of the caregivers reported spending at least 46 hours per week assisting patients with daily activities that ranged from preparing their meals to bathing and dressing them.

“This study gives us insight into the experiences of many of the 6 million people who provide long-term, unpaid care to disabled elderly persons in their families,” said Schulz, who also is director of the University Center for Social and Urban Research and associate director of Pitt’s Institute on Aging.

“The service these people provide saves the health care system billions of dollars a year, while the caregivers themselves endure both emotional and financial stress. Because the number of people in this situation will increase markedly over the next two decades, this study should serve as notice that we as a society may need to reassess how we support family caregivers.”

The study also examined depressive symptoms of 180 caregivers whose relatives were institutionalized. “Caregivers of patients who were institutionalized did not experience the improvement in depression that we observed among those whose relatives had died,” said Schulz.

The findings are from the Resources for Enhancing Alzheimer’s Caregiver Health (REACH) study, funded by grants from the National Institute on Aging and the National Institute for Nursing Research.

Among the study’s other authors were Pitt’s Aaron B. Mendelsohn, Song Zhang and Steven H. Belle.



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