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May 25, 2006


Promising new vaccine approach found

The field of vaccine development is getting a boost from new research that has identified a promising approach in which a lentivirus is used to deliver the vaccine. This method has produced long-term immune protection after just one immunization in animal studies.

Pitt researchers, who report their findings in the journal Immunity, say the method has particular relevance for efforts aimed at preventing or controlling infectious diseases such as HIV or influenza, or stopping the growth of cancer. In one set of studies using this delivery approach, a single immunization halted the progression of melanoma and significantly extended survival in a mouse model. In the next three to five years, researchers expect to initiate a clinical trial of the approach, most likely for patients with melanoma.

The approach makes use of an inactivated retrovirus, in this case, a modified lentiviral vector more commonly known for its ability to carry functional genes in certain types of gene therapy. Viral vectors in general have been of practical interest to vaccine researchers for their potential to deliver antigens from disease-causing microbes, or even cancer, in order to efficiently build immune defenses against such intruders.

To date, the lentivirus has been overlooked in vaccine research. But, according to Pitt investigators, it has distinct advantages that make it a more promising approach for vaccine development than other viral vector or DNA-based vaccine approaches previously studied.

According to results of their studies, a single injection of the lentivector containing either a hepatitis B virus antigen, a melanoma tumor antigen, or a commonly studied model antigen induced a stronger and long-lasting immune response compared to other immunization approaches.

A population of specialized immune cells that reside within the top layers of the skin is due much of the credit, say the authors.

“Skin dendritic cells have long been considered the immune system’s first line of defense,” said Louis D. Falo Jr., professor and chairman of dermatology in the School of Medicine, and the study’s senior author. “But recent studies that looked at different viral vectors, including the most commonly studied vaccinia vector, have challenged this notion, suggesting that skin dendritic cells are not as important as the classical paradigm maintained. We find that with the lentivirus, it’s precisely these skin dendritic cells that are responsible for the vector’s more potent immune induction and sustained protection.”

Because they exist on the surface of the skin, these cells are the first to recognize the presence of a foreign body, or antigen. Although no longer an active virus, the lentivector is cause enough for alarm, so the dendritic cells capture the vector and the antigens within and carry them to the lymph nodes, where T cells generate the immune response that attacks the invaders.

Importantly, the investigators found that despite being a foreign intruder itself, the lentivirus seemed to escape the notice of the immune system, even when introduced a second time, suggesting that it could be used repeatedly in the same patients.

“You might say the other viral vectors are a one-shot deal because the immune system recognizes the virus and responds against it the second time around,” said Falo. “With lentivirus, it seems feasible to use the immunization approach multiple times in the same patient, such as for annual flu vaccination, or in preventing multiple different infections or cancers in the same patient or in the general population.”

Other authors of the study are Yukai He of dermatology and immunology, and Jiying Zhang and Cara Donahue of dermatology.

The research was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institute of Allergy and Infectious Diseases and the National Cancer Institute.


Prenatal alcohol exposure linked to lower IQ in black children

Light-to-moderate drinking while pregnant can have damaging effects on cognitive development, lowering IQ scores in African-American children at age 10, according to a study published by School of Medicine researchers in the journal Alcoholism: Clinical & Experimental Research.

While researchers have found that heavy drinking during pregnancy leads to lower intelligence in children, fewer studies have focused on the effects of light-to-moderate levels of alcohol exposure. This study found that in 10-year-old African Americans, exposure to between two and six drinks per week during pregnancy, especially in the second trimester, was associated with a lower IQ score compared to children who were not exposed to alcohol prenatally. There was no association found in Caucasian children. Binge drinking was less important than the overall level of exposure over time in predicting the effect alcohol would have on the child.

“If light-to-moderate drinking can lower IQ, it suggests that mothers should try to abstain during their pregnancies to prevent their children from having cognitive deficits,” said Jennifer A. Willford, assistant professor of psychiatry in the School of Medicine and lead author of the study.

This study used data from the Maternal Health Practices and Child Development Project, an examination of prenatal substance abuse in women who attended a prenatal clinic from 1983 to 1985 in which women were assessed during each trimester of pregnancy, and again with their children at birth, eight months, 18 months, and at three, six, 10, 14, 16, and 21 years of age. At 10 years of age, the children’s cognitive ability was assessed using the Stanford Binet Intelligence Test.

After normalizing the data to account for factors also known to predict cognitive ability, including maternal intellectual ability, maternal drug use, psychosocial characteristics, socio-economic status and home environment, researchers were able to understand how prenatal alcohol exposure lowered IQ within the context of other risk factors that might lead to cognitive deficits. They found a relationship between low-to-moderate alcohol exposure during the first and second trimester and intelligence at age 10 in African-American children, but no relationship in Caucasian children.

“Our results indicate that the differences in prenatal alcohol effects on the IQ scores of African-American and Caucasian children were not due to the amount or pattern of drinking during pregnancy, their socio-economic status, or the education levels of the parents. We cannot say why this racial difference exists, but other laboratory animal and human studies suggest that genetics may play a role,” said Willford.

Co-authors of the study are Sharon L. Leech of UPMC and Nancy L. Day, professor of psychiatry in the School of Medicine.

The study was funded through grants from the National Institute of Alcoholism and Alcohol Abuse and National Institute on Drug Abuse.


Study finds no rise in breast cancer risk with statins

A report being published in the Journal of the National Cancer Institute found that women who took statins -— the widely used cholesterol lowering drugs — do not face an increased breast cancer risk as had been suggested by some previous studies.

And, for some women, a new study led by a researcher at Pitt’s Graduate School of Public Health (GSPH), found that women who took hydrophobic statins had an almost one-fifth lower incidence of invasive breast cancer compared to women who did not take statins.

“At minimum, our findings suggest that women can now be reassured that they are not increasing their risk of developing breast cancer by taking these drugs,” said senior author Jane Cauley, professor and vice chair for research, Department of Epidemiology, GSPH.

“Although we found that women who took hydrophobic statins actually lowered their breast cancer risk, we believe this finding needs to be confirmed in additional studies.”

Cauley and her colleagues, representing several other research institutions, obtained their findings by analyzing breast cancer incidence over an almost seven-year period among more than 156,000 women enrolled in the long-running Women’s Health Initiative study. Of this group of post-menopausal women, 11,710 were statin users; with about 30 percent taking a hydrophilic, or water-soluble, statin, and the remaining 70 percent taking a hydrophobic, non-water-soluble statin.

During the follow-up period, 4,483 women in the study were diagnosed with invasive breast cancer. When the research team examined statins as a class, they found no statistically significant association between statin use and breast cancer incidence, although statin users did tend to have somewhat lower breast cancer rates than non-statin users.

Breast cancer incidence also was not associated with how long statins were used. Moreover, use of post-menopausal hormone therapy did not modify the association between statin use and breast cancer.

However, when the investigators analyzed breast cancer rates by type of statin, they found that among women taking any of several hydrophobic statins, there was an 18 percent decreased incidence of breast cancer compared to non-users of statins and that this difference was statistically significant.

Cauley notes that finding a link between hydrophobic statins and reduced breast cancer risk is consistent with the results of several other recent studies. One, a cell culture study, found that hydrophobic statins inhibited the growth of several breast cancer cell lines, while a hydrophilic statin did not. In addition, another study reported a 72 percent lower risk of breast cancer in a small group of women, most of whom were taking hydrophobic statins.

“A number of different mechanisms have been identified by which this class of statins might inhibit the growth of cancer. For example, animal studies have shown that hydrophobic statins induce programmed cell death, or apoptosis. Hence, there certainly is some biological plausibility for this class of statins preventing cancer,” said Cauley. However, she cautions that further research is needed to determine whether hydrophobic statins actually can inhibit breast cancer in humans.

This study was funded by the National Heart, Lung and Blood Institute, National Institutes of Health.


Substrates affect the motion of soft capsules

Anna C. Balazs, Distinguished Professor of Chemical and Petroleum Engineering, is among the authors of a paper that models how the motion of soft matter is affected by the surface on which it rolls. The article appears in the journal Chemical Science.

The research could be used to design surfaces that can control separation between capsules of soft matter. Such surfaces could be used to control the motion of cells or polymeric microcapsules, and could be useful in tissue engineering or biological assays.

The team studied the motion of pairs of capsules (modeled as fluid-filled elastic shells to represent cells or polymeric microcapsules) on various surfaces.

They found that the interactions between the capsules are mediated by the nature of the underlying layer. The research showed that the relative and the average velocities of a pair of closely spaced rolling capsules depend on the elasticity of the capsules, the adhesive interaction between the capsules and the surface, and the substrate itself.

They found that, on a stiff surface, pairs of rigid capsules always separate from one another, while soft capsules are affected by the strength of the adhesive interaction with the surface.

If they adhere strongly to the substrate, they roll away from one another. If adhesion is weak, the capsules actually approach each other.

“In the case of soft substrates, any significant deformations of the surface that are caused by the capsules give rise to a force that propels the particles to move rapidly apart,” the research showed.

In cases of strong adhesion between the capsules and the soft substrates, both rigid and flexible capsules are driven to separate. But, for weak adhesion, the elastic particles approach each other, acting similar to their behavior on stiff surfaces.


Microscope funded for pharmaceutical sciences

Robert Gibbs, associate professor of pharmaceutical sciences at the School of Pharmacy, has been awarded a shared instrumentation grant of nearly $300,000 by the National Institutes of Health (NIH) for the purchase of a new microscope.

Drug discovery researchers in the School of Pharmacy and School of Medicine will use the new Zeiss 510 Meta Confocal Microscope to aid in the development of anti-cancer agents and gene therapy methodologies.

In his funding request to NIH, Gibbs stated that the School of Pharmacy has no confocal instrument of its own and is forced to share instrument time on microscopes elsewhere in the University.

Gibbs said School of Pharmacy personnel often have to wait weeks for time slots on microscopes in other departments and frequently have insufficient time to analyze and collect all the data they need, delaying the pace of research.

He added that the lack of equipment presents an obstacle to recruiting research faculty and that a half-dozen NIH-funded investigators at the school had identified a need for the equipment, which will be housed on the 10th floor of Salk Hall.


Urology research presented

Pitt researchers recently presented the results of more than 50 studies at the annual meeting of the American Urological Association in Atlanta. Among the highlights:


Herb, marijuana ingredient may relieve bladder pain

Two separate studies have found St. John’s Wort, an herbal supplement used to treat depression, and IP 751, a synthetic analog of a metabolite of THC, the principal active ingredient of marijuana, may be effective in relieving pain that occurs in hypersensitive bladder disorders such as interstitial cystitis.

Prior studies have found that serotonin- and norepinephrine-emitting neurons control the neurology of the lower urinary tract. These neurons are similar to those that play a role in depression and anxiety.

“St. John’s Wort is an herbal supplement that has been used for years to treat symptoms of mild depression, while urologists often use antidepressants to treat interstitial cystitis,” said Michael B. Chancellor, professor of urology and gynecology at the School of Medicine. “Given that the supplement and the drug work on the same systems, it makes sense that St. John’s Wort could help treat this painful disease.”

For the study, Pitt researchers injected a formulation of St. John’s Wort into the abdomens of rats with bladder inflammation. Bladder hyperactivity, marked by frequent bladder contractions, is a significant cause of irritation and pain. Compared with controls, these rats showed less frequent contractions.

In a separate study, Chancellor found similar results using IP 751, a potent anti-inflammatory and a powerful analgesic, although the mechanisms by which it works are unknown.

Because the drug is insoluble in water, it is difficult to administer directly to the bladder. To overcome this difficulty, Chancellor’s team introduced the drug into a liposome — a tiny sac surrounded by fatty acids — allowing it to be delivered into the bladders of rat models with varying degrees of bladder inflammation. In both animal models, IP 751 significantly suppressed bladder overactivity — the underlying cause of irritation and pain in the bladder.

“Interstitial cystitis is a difficult disease to treat, and not all treatments work well on all patients,” said Chancellor. “Any new option we can give our patients to alleviate their painful symptoms is very important.”


Stem cell injections improve continence

In the first clinical study of its kind in North America, women with stress urinary incontinence (SUI) were treated using muscle-derived stem cell injections to strengthen deficient sphincter muscles responsible for the condition. Results of the study, led by researchers at Pitt’s School of Medicine and Sunnybrook Health Sciences Centre in Toronto, suggest that the approach is safe, improves patients’ quality of life and may be an effective treatment for SUI.

Women with SUI involuntarily lose urine during activities that put pressure on the bladder, such as running, coughing, sneezing or laughing. Stress incontinence is caused by childbirth, menopause or pelvic surgery and is most often diagnosed in women during middle age.

Previous animal studies at the School of Medicine that formed the basis for the clinical trial showed that injecting stem cells into the urethral muscles of animal models with SUI increased leak point pressure, leading to a restoration of the deficient muscles.

“Our preliminary findings in this clinical trial are extremely encouraging, given that 13 million people, most of them women, cope with stress urinary incontinence in the United States,” said Michael B. Chancellor, the study’s senior author and professor of urology and gynecology at the School of Medicine. “We’re demonstrating for the first time that we may be able to offer people with SUI a long-term and minimally invasive treatment.”

In the study, researchers took biopsies of skeletal muscle tissue from seven female patients and isolated and expanded the stem cells from the tissue in culture. In an outpatient setting, the patients then received injections of the muscle-derived stem cells into the area surrounding the urethra. Each patient received an equal dose of stem cell injections using three different injection techniques — a transurethral injection with either an 8-mm or 10-mm needle or a periurethral injection.

Five of the seven women who participated in the study reported improvement in bladder control and quality of life with no serious adverse effects. These improvements were associated with both the 10-mm needle injections and the periurethral injections, which allowed the investigators to deliver the stem cells close to the damaged sphincter muscle. The 8-mm needle was not able to deliver the muscle stem cells deep enough into the tissue to reach the sphincter.

A follow-up multi-site study set to launch this summer will allow researchers to determine the optimal dose of muscle stem cells.

Other Pitt contributors to the study were David Wagner, Ryan Pruchnic, Ron Jankowski, Janet Erickson, Fernando de Miguel, Naoki Yoshimura and Johnny Huard of the School of Medicine.

The study was funded by Cook MyoSite Inc. of Pittsburgh.


Botox helps relieve enlarged prostate symptoms

A study of 41 men with benign prostatic hyperplasia (BPH), more commonly known as enlarged prostate, found botulinum toxin A (Botox) injections eased symptoms and improved their quality of life.

“Millions of men in the United States suffer from enlarged prostate,” said Michael B. Chancellor, professor of urology and gynecology at the School of Medicine.

BPH affects more than half of all men over the age of 60, and 80 percent by age 80. Symptoms include more frequent urination, urinary tract infections, the inability to completely empty the bladder and, in severe cases, eventual damage to the bladder and kidneys.

“It’s a challenging disease to live with because it causes frequent and difficult urination. Unfortunately, common treatments also are problematic because they carry some risk of serious side effects, such as impotence. Our results are encouraging because they indicate that Botox could represent a simple, safe and effective treatment for enlarged prostate,” Chancellor said.

In the study, researchers at the Chang Gung University Medical College, Taiwan and the Pitt School of Medicine injected Botox directly into the prostate glands of men with symptomatic BPH that did not respond to standard medical treatment. Of 41 patients, 31, or 75.6 percent, experienced a 30 percent improvement in urinary tract symptoms and quality of life. These improvements continued for up to a year in some patients.

Four out of five patients were able to completely empty their bladders within a week to one month after the injection, as the Botox caused the prostate gland to relax, putting less pressure on the urethra. Patients did not experience any significant side effects, including stress urinary incontinence or erectile dysfunction.

Chancellor said Botox reduces the size of the prostate gland through a cellular process called apoptosis, in which the prostate cells die in a programmed manner. This reduction in size can improve urine flow and decrease residual urine left in the bladder.

Other Pitt researchers involved in the study were Naoki Yoshimura and Fernando de Miguel, of the School of Medicine.

The study was funded by a grant from Allergan.


Health science researchers awarded grants

A number of researchers in the Pitt Schools of the Health Sciences recently have received government and private sector funding to further existing studies or pursue new research. Among them are:


Racial disparities in breast cancer outcomes to be studied

Margaret Rosenzweig, assistant professor in the acute and tertiary care department at the School of Nursing, has received a three-year, $250,000 grant from the Susan G. Komen Breast Cancer Foundation to develop and evaluate an intervention that will address a number of the issues that prevent African-American women from completing a full course of chemotherapy treatment.

African-American women face significantly poorer outcomes following breast cancer diagnosis than their Caucasian counterparts do.

In this study, Rosenzweig will address whether part of the gap may be due to discrepancies in chemotherapy doses resulting from factors such as adherence and symptom management.

The intervention will address adherence to appointments and treatment; cross-cultural communication with health care providers, and access to individualized treatment-related information such as the over-expression of the HER2 protein, which is found in more aggressive breast cancers.

In the project’s first phase, two focus groups — one of African-American women currently undergoing chemotherapy for breast cancer, and the other consisting of patients one year removed from treatment — will evaluate the intervention and provide feedback on its structure, content and messages.

The second phase will involve a pilot of the intervention involving 20 women who will receive education and counseling from an African-American breast cancer survivor upon their first medical oncology visit and for up to six months afterward.


Teen anti-smoking study funded

Brian Primack, an assistant professor in the Division of General Internal Medicine in the School of Medicine, will receive $300,000 over three years as one of 15 inaugural Robert Wood Johnson Foundation Physician Faculty Scholars. The program funds promising young physicians pursuing careers in academic medicine.

The grant will further Primack’s research on the relationship between media literacy and smoking behaviors in teenagers.

In this project, Primack will conduct a randomized trial comparing a traditional school-based anti-smoking curriculum to a media literacy-based anti-smoking curriculum. Students’ smoking-related attitudes, intentions and behaviors will be measured over time.

Primack’s mentors for the project were Michael Fine, professor of medicine, and Melanie Gold, associate professor of pediatrics.

This multidisciplinary project also will utilize the talents of School of Medicine measurement specialist Galen Switzer and School of Education health education specialist Carl I. Fertman.


Grant aims to improve brain circuitry in people with schizophrenia

David A. Lewis, professor of psychiatry and neuroscience, and director of Pitt’s translational neuroscience program, has received a Freedom to Discover grant from Bristol-Myers Squibb to explore the effects of enhancing the function of neural circuits in the brain in order to improve cognitive abilities in individuals with schizophrenia.

Freedom to Discover grants are unrestricted and provide researchers with $500,000 over five years to support any scientific endeavor of their choosing. A dozen of these grants were awarded this year.


Study of protein degradation funded

Regulation of cellular protein concentration, largely a function of the balance of protein synthesis and degradation, is critical to proper cellular function. While many labs research the production of proteins, Yong Tae Kwon, assistant professor of pharmaceutical sciences at the School of Pharmacy, has turned his attention to their decomposition.

Kwon’s area of focus is the N-end rule pathway, in which proteins are marked for degradation when a recognition complex identifies the final amino acid in the peptide chain, or n-terminus, as a signal that the protein should be destroyed. The process depends on a small protein known as ubiquitin, which is attached to the protein as a tag that communicates its fate to the degradation structure, or proteasome.

Previously, Kwon was able to identify seven proteins as critical in the recognition structure based on a common strand of 70 amino acids found in each protein.

Kwon has received a five-year, $1.1 million grant from the National Institutes of Health to investigate this process further. In addition to examining the biochemical properties of ubiquitin and its role in degradation, Kwon also plans to study the properties of substrates in which the breakdown of proteins is able to proceed.

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