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June 12, 1997


Computer science prof gets NSF Career Grant

Mark Moir, assistant professor of computer science, has been awarded a four-year National Science Foundation Career Grant of $204,975 for his proposal, "Transparent Support for Efficient, Wait-Free Transactions in Shared-Memory Multiprocessors." Multiprocessor computers are increasingly popular for a wide variety of computation-intensive applications ranging from cryptography to speech recognition. Interactions between multiple processors in such applications make them much more difficult to program than traditional uniprocessor applications, especially when the possibility of failures is considered. Moir's research aims to relieve programmers of these burdens while improving application performance.


Cancer Institute establishes Cyert Chair

The University of Pittsburgh Cancer Institute (UPCI) has established the Richard M. Cyert Chair in Molecular Oncology. UPCI will recruit an internationally recognized expert in molecular genetics of cancer for the position and to oversee establishment of a Center for Molecular Oncology.

Cyert, president emeritus of Carnegie Mellon University, is a UPCI patient and serves on the UPCI Council, an advisory board made up of community leaders.

Pitt received $1.5 million, half from the Vira I. Heinz Endowment and half from the H.J. Heinz Company Foundation, to establish the chair.


Researchers from WPIC receive NARSAD grants

Four researchers from the Western Psychiatric Institute and Clinic have received grants totaling $240,000 from the National Alliance for Research on Schizophrenia and Depression (NARSAD).

Jair C. Soares, senior resident in the psychiatry department, is measuring membrane phospholipid levels in blood platelets to determine the effects that the drug lithium has in selected membrane phospholipids in patients with bipolar disorder, which is characterized by swings in mood from depression to mania. Soares' research may lead to a better understanding of the biological mechanisms that cause bipolar disorder, and how lithium works in treating patients with the disorder.

Ravinder Reddy, assistant professor of psychiatry, is seeking to learn if schizophrenic patients who do not respond well to treatment may be identified by a specific, potentially reversible, chemical change in the membranes of brain cells. If this is true, Reddy's findings could lead to the development of novel treatments that result in more favorable outcomes for schizophrenic patients.

Cameron S. Carter, assistant professor of psychiatry, is using positron emission tomography to examine the function of the anterior cingulate gyrus, an area of the frontal lobe of the brain that plays an important role in cognitive functions. Schizophrenia patients have cognitive deficits that impair their ability to function normally, yet current treatments have little or no impact on this aspect of the illness. The anterior cingulate is abnormal in schizophrenia, but the role these abnormalities play in cognitive disturbances is not yet understood. Carter's study will help define the significance of abnormalities of the anterior cingulate gyrus and lay the foundation for further work directed towards developing effective treatments for the cognitive symptoms of schizophrenia.

Beatriz Luna, postdoctoral fellow in psychiatry, is using functional magnetic resonance imaging to look at normal brain development in children ages 8 to 17, a crucial period when disorders like schizophrenia often emerge. Luna's research will provide a backdrop for further research into developmental problems that may lead to schizophrenia.

Money for the NARSAD grants was donated by people with mental illnesses, their families, friends and colleagues, to support studies to improve the understanding and treatment of severe mental illness.


Interacting with spouse lowers blood pressure, research shows

In one of the first studies of its kind, Pitt researchers have found that interacting with one's spouse can lower one's blood pressure, at least in the short run, compared to being alone or interacting with others.

Pitt psychology professor Thomas Kamarck says preliminary findings show that participants in the study had comparatively lower blood pressure readings during spousal interaction, whether in distressed or non-distressed marriages. The study's purpose was to determine how a variety of psychological variables, including spousal interaction, affected short-term blood pressure. Interaction was defined as a give-and-take exchange with another person, not necessarily involving verbal communication.

The study also revealed that in spousal interaction involving conflict, men showed significant increases in blood pressure, compared to women. "Women tend to be more straightforward in expressing negative feelings than do men," Kamarck said. "With their wives, men tend to be less confrontational. There is evidence that when a person is provoked and doesn't express anger, his or her blood pressure may stay elevated longer. So this difference in blood pressure responses to social conflict could be a function of differences in typical expressive styles of men and women, but that is speculative at this point." The data also showed that distressed couples spend less time interacting with their spouses and a higher proportion of their interaction was conflictual.

Each of the 120 participants (50 percent African-American, 50 percent female) wore an ambulatory blood pressure cuff continuously throughout normal daily activities for six days. The device automatically inflated every 45 minutes to record the subject's blood pressure, at which time participants entered information into an electronic hand-held diary, including whether or not they were interacting with someone, with whom, for how long, if demands were being made on them, if they were being ignored, etc. Researchers adjusted for extraneous factors such as posture and movement, on a case-by-case basis.

Why did blood pressure levels drop? Kamarck is conducting an additional analysis of the figures. "We're trying to determine if the readings have to do with the safety of a close or confiding relationship," he explained. "It's possible, but speculative, that these findings could contribute in part to the explanation of earlier findings relating marital status to the tendency to live longer."


UPJ professor awarded grant

Elisabeth Bell-Loncella, assistant professor of chemistry at the Johnstown (UPJ) campus, has received a two-year, $25,000 grant from the Petroleum Research Fund of the American Chemical Society. The grant will fund summer stipends for two UPJ chemistry undergraduates and help to purchase an electrochemical analyzer.


Discovery may hold key to treating alcoholism, cancer

Research by a three-university team — including a Pitt group — has identified the molecular structure of a protein that may lead to development of medical treatment that could produce effective treatment of alcohol abuse and alcoholism without serious side effects and assist in enhancing performance of cancer drugs.

Pitt researchers led by John Hempel, associate research professor of biological sciences and a member of the University of Pittsburgh Cancer Institute, have described the three-dimensional structure of the aldehyde dehydrogenase (ALDH), a protein that removes the highly toxic acetaldehyde generated during the metabolism of alcohol. High levels of acetaldehyde in the body are implicated in many of the harmful effects of excessive alcohol consumption, including cirrhosis of the liver and fetal alcohol effects.

Eliminating aldehydes is crucial to the health of living cells. In addition, some forms of ALDH neutralize certain drugs in cancer chemotherapy. Blocking the enzyme's ability to inactivate chemotherapeutic agents would mean that these drugs could be used effectively in treating more types of cancer.

Researchers from the University of Georgia and the University of South Dakota also participated.

UPCI researchers present findings at AACR meeting University of Pittsburgh Cancer Institute (UPCI) investigators presented the following research findings at the annual meeting of the American Association for Cancer Research in San Diego, last spring.


Retrovirus can transform normal pigment-forming cells into melanoma

A retrovirus that was isolated from mouse melanomas can transform normal mouse melanocytes into melanoma cells, according to UPCI researchers. "This is the first evidence that a retrovirus can cause the development of melanoma," said Pitt pathology professor Elieser Gorelik.

Melanocytes are the skin's pigment-forming cells that become malignantly transformed into life-threatening melanoma, the underlying causes of which remain obscure. The incidence of melanoma is increasing more rapidly than any other cancer.

The melanoma-associated retrovirus belongs to the family of mouse leukemia viruses that has been shown to induce leukemia and lymphoma in mice. These retroviruses do not contain an oncogene, or cancer-causing gene. Thus, researchers speculate that the melanoma-associated retrovirus inserts itself randomly into a normal melanocyte's genetic material. There, it somehow upsets normal cellular genetic activity, perhaps by triggering the abnormal expression of one of the cell's own oncogenes or by interfering with a cell's tumor suppresser gene, which normally prevents the cell from becoming cancerous. As a result, normal melanocytes might undergo malignant transformation.

The researchers' current goal is to discover which cellular genes the virus is disturbing. "Once we have this information, we can look at human melanomas to determine whether the same cellular genes are also acting incorrectly. These findings can help us understand the molecular mechanisms underlying melanoma in people," Gorelik said.


Vitamin D may have potential for treating prostate cancer

Vitamin D significantly inhibits highly metastatic, or widespread, prostate cancer in animals, suggesting that it has potential for treating men with similarly advanced disease.

"This is the first evidence that vitamin D can effectively treat an animal with advanced prostate cancer that spreads to the bone, similar to what happens in men affected with this disease," said Ben Light, a researcher with UPCI's Experimental Therapeutics Program.

In their study, UPCI researchers implanted highly metastatic prostate tumors into rats and treated them with vitamin D. After three weeks of therapy, tumors in treated rats were 88 percent smaller than those in control group rats that were implanted with tumors but were not treated. In addition, the treated rats had 75 percent fewer lung metastases, and those metastases were 85 percent smaller than those seen in untreated control animals.

Past studies by UPCI scientists and others have shown that old age, black race and residence in northern latitudes — known risk factors for prostate cancer — all correlate with low blood levels of vitamin D. Recently, they have shown that vitamin D may be involved in the growth and differentiation of the normal prostate. Vitamin D binds to cancer cells and triggers either cancer cell death or the transformation of cancer cells into more benign cells.

UPCI clinical investigators are incorporating vitamin D in early clinical studies for advanced prostate cancer as well as other tumors.


Natural genetic variations in drug metabolizing enzymes contribute to cancer development

Naturally occurring genetic variations in drug metabolizing enzymes significantly contribute to whether a person develops certain cancers, according to recent UPCI studies.

The enzymes, called cytochrome P450s (CYPs) and phase II enzymes, normally break down chemicals entering the body. Slight variations in the gene for a given enzyme result in different forms of that enzyme, each form performing the same function but at a different rate. Because of these genetic differences, individuals metabolize foreign substances differently from one another.

"Individuals with certain genetic profiles or a history of certain environmental exposures are strongly at risk for head and neck cancer," said Marjorie Romkes, Pitt assistant professor of environmental and occupational health and toxicology. Elevated activity of one enzyme (CYP2E1), low activity of another (CYP2C19), smoking, alcohol consumption and occupational exposures independently place individuals at increased risk for head and neck cancer, according to preliminary findings.

"Certain enzyme genotypes in people without cancer appear to be associated with DNA damage that could lead to cancer," said Romkes in regard to another presentation showing that normal human cells with certain enzyme forms showed higher levels of DNA mutations than human cells with different enzyme forms.

Another UPCI project indicates that persons with bladder cancer who had p53 mutations either had a history of exposure to a cancer-causing substance or abnormalities in enzymes that process environmental chemicals. The gene p53 normally suppresses tumor growth. When mutated, the p53 gene cannot function correctly and cancer arises. Researchers suspect that p53 mutations are involved in about half of all cancers.

Some CYPs remove cancer-causing agents by turning them into benign chemicals within the body. Researchers aim to develop drugs that would accelerate the activity of these enzymes in patients whose enzymes naturally work very slowly. Other CYPs do the reverse, taking procarcinogens (potentially cancer-causing substances) and turning them into cancer-causing chemicals that linger in the body, where they can cause damage. Pitt investigators are working with drugs to block or slow the activity of these enzymes in persons who have enzymes that rapidly produce such cancer-causing substances.


Pitt researchers participate in landmark study of early child care

Placing an infant in child care neither adversely affects — nor does it promote — the security of the child's attachment to his or her mother. But low-quality child care, combined with a mother's insensitivity, can have an adverse effect.

That is one of the findings to date of a national study on child care, in which Pitt researchers are participating. The University is one of 10 national sites taking part in the National Institute of Child Health and Human Development Study of Early Child Care.

Pitt's leading researchers on the project, psychology professor Susan Campbell and Celia Brownell, associate professor and chairperson of the University's developmental psychology program, have been studying 120 local families since 1991. Children were assessed at one, six, 15, 24, 36 and 54 months, at home, in child care, in the laboratory playroom and in kindergarten. The first-grade assessment begins this fall, making this one of the most comprehensive studies of child development.

Among the other findings:

* Quality child care in the early years, with a high degree of interaction between caregivers and children, is associated with more positive and engaged mother-child interaction.

* The amount of language stimulation in child care is associated with a child's better cognitive development and language functioning as a toddler.

* Across all measures, what happens in the family setting remains the most important predictor of cognitive outcomes and the mother-child relationship, even for children in full-time child care.


Scientists propose new perspective on HIV infection

A provocative new scenario of T cell activity in HIV infection challenges the biological reasoning and the mathematical approaches underlying two existing models of T cell decline in AIDS patients, according to an analysis by investigators from Pitt and Tel Aviv University.

The analysis was published last month in Nature Medicine.

The new analysis, which could suggest other treatment approaches, stresses several novel aspects of HIV infection, including a distinct adaptive response of the body's immune system to the virus that renders many CD4 T lymphocytes, the most vulnerable target, variably resistant to HIV infection. The analysis also suggests that cell types other than CD4 cells play an important role in sustaining the infection, not only as additional reservoirs of HIV but as part of the primary mechanism of HIV transmission among cells.

One model that the new report challenges, called "failing homeostasis," was proposed in 1995. At that time, when antiviral drugs were effectively used in patients to block continued infection of cells by HIV, the subsequent initial rise of CD4 cells in these patients was explained as a result of the rapid production of CD4 cells that existed before the treatment, and that now after treatment exceeded cell loss. Based on this interpretation, scientists estimated a rapid turnover rate of CD4 cells before treatment.

"Failing homeostasis" purports that HIV vigorously destroys CD4 cells from the outset of infection. Although the body initially can keep up and replace lost cells, maintaining a fairly stable steady state for several years, the highly accelerated CD4 cell turnover, according to this view, eventually exhausts the so-called homeostatic capacity of the immune system for maintaining its size and integrity. Inability to replace the lost cells quickly enough, during the time when patients have become infected with HIV but show no symptoms, is responsible for the falling CD4 cell counts and is also the direct cause of AIDS. But the reasoning for the "failing homeostasis" model is unsound, say the authors of the Nature Medicine paper.

"In fact, the turnover of CD4 cells need not be considered out of the ordinary," said Zvi Grossman, senior lecturer of physiology and pharmacology at Tel Aviv University and adjunct professor of biostatistics at Pitt. "Advances in understanding the immune system as a complex dynamic system, which manifests flexibility and adaptability in several ways, strongly suggest that the rise in CD4 cells after drug treatment for HIV infection is not the result of overproduction of these calls, a process already in motion, but rather an adaptive response to the decrease in virus. We and other investigators believe, for example, that CD4 cells are released into the bloodstream from other compartments. More importantly, the decline in CD4 cell counts, which is the hallmark of HIV infection, also reflects, in large part, an adaptive response rather than simply resulting from cell depletion." Consideration of the possible physiological purpose of such adaptive response, from this perspective, points to possible innovations in treatment for HIV infection.

Co-author Ronald Herber-man, director of the University of Pittsburgh Cancer Institute and Pitt associate vice chancellor for Health Sciences, said: "Current models of HIV infection do not adequately take into account some basic aspects of T lymphocyte response to stimulation, which have been studied and conceptualized in recent years and which suggest that CD4 cells chronically exposed to HIV and to HIV-induced factors can become resistant to infection. Such resistance is associated with a reduced ability of the cells to proliferate and circulate, which may partly explain the reduced levels of CD4 cells in the blood. Most researchers consider only conditions in which HIV exposure stimulates CD4 cell division and infection. We call the two concomitant processes 'differential activation.' Differential activation also points to novel ways of treating infection, perhaps by selectively promoting the generation of resistance in those CD4 cells that are more likely to become infected with HIV." Another relatively unexploit-ed target for anti-viral therapy is the reservoir of macrophages and other non-CD4 cells located in lymph tissue. Some of these cells become infected with HIV, although they contribute little to the virus load. Here again the authors question the mainstream view. "These other cells and other modes of infection may be as essential for sustaining the disease as the infection of CD4 T cells, because they live longer after being infected and because they are directly involved in cell-cell interactions whereby CD4 cells are activated and become susceptible to infection," Grossman said.


Musculoskeletal researchers honored

The American Orthopaedic Society for Sports Medicine (AOSSM) has awarded its 1997 O'Donoghue Sports Injury Research Award to a team of researchers from the UPMC Musculoskeletal Research Center. The award is the highest and most prestigious given by AOSSM.

The award was given for the project, "Growth Factors Can Improve MCL (medial collateral ligament) Healing in Vivo." Pitt researchers participating in the project included Kevin Hildebrand, Savio Woo, David Smith, Christina Allen, Masataka Deie, Brian Taylor and Christopher Schmidt.

Their work showed that the presence of growth factors at the site of a complete MCL tear can reduce the size of the scar tissue mass and improve the histological and biomechanical quality of the healing tissue. Future work will examine the efficacy of growth factor delivery using gene therapy.


Gene therapy using IL-12 reduces tumors in patients with advanced cancer, UPCI research shows

Injecting cells genetically engineered with the genes of the hormone-like substance, interleukin-12 (IL-12), can significantly reduce tumors in some patients with advanced cancer, according to University of Pittsburgh Cancer Institute researchers.

The results were based on the first gene therapy trial using IL-12 for patients with breast cancer, melanoma, thyroid cancer or head and neck cancer.

"We were very pleased and somewhat surprised to see that the first attempt at IL-12 gene therapy successfully reduced tumors in 28 percent of patients treated," said Michael Lotze, who is the study's principal investigator as well as co-director of UPCI's Biologic Therapeutics Program and professor of surgery and molecular genetics and biochemistry.


UPJ professor gets grant

Stephen Kilpatrick, assistant professor of biology at the Johnstown campus, has received a $10,429 University of Pittsburgh Research Council grant to research his proposed project, "Molecular Population Genetics of Drosophila melanogaster.


Prozac may be first effective drug treatment for anorexia nervosa

Prozac may help people with anorexia nervosa maintain healthy body weight, according to results of a UPMC study.

The study is the first to suggest that an antidepressant may prevent a relapse into anorexia, said the study's principal investigator, Walter H. Kaye, professor of psychiatry at Western Psychiatric Institute and Clinic.

Anorexia nervosa is the most deadly psychiatric disorder. There is no medication currently approved to treat it. Patients starve themselves in a relentless pursuit of weight loss and have accompanying symptoms such as depression, anxiety, obsessions and compulsions. Research indicates these symptoms may be linked to disturbances in serotonin, a neurotransmitter that helps regulate mood and appetite. Prozac may work be stabilizing serotonin systems in the brain, correcting the changes in brain function responsible for many of the disorder's symptoms.


Working memory may operate outside of conscious awareness, UPMC and Carnegie Mellon researchers say

Research at UPMC and Carnegie Mellon University identifies regions of the brain that allow learning to take place without the person being consciously aware of it.

The results could change the way researchers view learning and may have implications for the treatment of certain disorders.

"Being able to learn and adapt to change subconsciously is an important function of the brain," said principal investigator Gregory S. Berns, resident in psychiatry at Western Psychiatric Institute and Clinic.

"People base their behavior on consistency, whether it's driving to work every day or investing in the stock market," Berns explained. "People who play the stock market, for example, often develop a hunch on how a stock is going to move, without being able to say exactly why they feel that way. They may do this because one part of their brain has formed expectations based on certain consistencies about the market while the other part is paying attention to what is actually happening moment to moment, both working on a subconscious level. These two parts of the brain share information and the investor forms a hunch." The area of the brain that researchers believe is responsible for learning consistencies and storing expectations is an area of the right prefrontal cortex, situated behind the forehead above the right eye.

Deep in the center of the brain, a part of the basal ganglia called the striatum seems to weigh what the cortex knows from experience against what is happening at that moment. If something in the environment changes, this system picks up on it and automatically, unconsciously, alters behavior accordingly.

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