University Times

Boosting immune response to HIV-1 is key to controlling infection,GSPH researchers say

Scientists at Pitt's Graduate School of Public Health have proposed a new and better approach to controlling HIV infection in AIDS patients.

Pitt research results suggest that combining current drug treatments to drive down levels of HIV-1, the virus that causes AIDS, with methods to boost immune responses to the virus may offer patients better long-term protection against HIV-1.

This is the first time a research study has shown that even small numbers of certain immune cells, called killer T cells because of their ability to kill HIV-1, can be boosted in laboratory dishes to seek out the virus.

The Pitt research team believes that finding ways to trigger and enhance the activity of these virus-killing cells in AIDS and HIV-infected patients will protect those persons against further exposures to the virus or reactivation of the virus hidden in parts of the body not reached by current drugs. It may one day allow patients to quit taking the drug combinations, which involve up to 18 pills a day. Future studies in monkeys and humans are planned.

Charles Rinaldo, chairperson of GSPH's Department of Infectious Diseases and Microbiology, announced the findings at the 12th World AIDS Conference in Geneva, Switzerland, this summer.

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Researchers probe genetic makeup of cancer patients and siblings

University of Pittsburgh Cancer Institute (UPCI) researchers are participating in a multicenter study to determine the relationship between genes and cancer development in patients and their siblings who have been diagnosed with the same type of cancer.

"Having certain genetic characteristics may make a person more likely to develop cancer. Through this study, we want to identify genes common to patients and their siblings diagnosed with either breast, colon, lung or prostate cancer and determine whether these common genes contribute to the development of cancer," said Wendy Rubinstein, principal investigator of the study at UPCI, interim director of the institute's Cancer Genetics Program, and an assistant professor at Pitt's medical school.

Researchers will use two methods to define genes associated with cancer. In the "fishing expedition" approach, they will screen the sibling pairs' genetic information against a battery of 100 or more genetic markers to determine whether any of these are shared among siblings with a given cancer. Researchers also will look at sibling pairs to learn whether specific "candidate genes," or genes that already are known to play a role in cancer development, are involved in development of the siblings' cancers.

"Only 5 to 10 percent of cancers in families are caused by a single predisposing gene such as BRCA1 in breast cancer," Rubinstein said. "The vast majority of cancers are caused by the interaction of several genes, and we don't yet understand the contribution of each of these genes to the development of a specific cancer type. We hope to gather this information through this latest study." For more information about the study or other clinical trials, call UPCI's Cancer Information and Referral Service at 1-800-237-4PCI (4724).

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Congestive heart failure drug studied

A cardiologist at UPMC Braddock is participating in a nationwide study of congestive heart failure patients to determine if a drug called Milrinone improves their quality of life.

An estimated 4.8 million Americans have congestive heart failure, in which the heart cannot maintain adequate blood circulation because it fails to pump blood properly. It is the chief cause of about 40,000 deaths in the United States each year and is a major contributing factor in an additional 225,000 deaths.

"Congestive heart failure is a costly diagnosis," said Stuart Tauberg, a cardiologist who is principal investigator of the study at UPMC Braddock. "If we can treat these patients more effectively with better medications and reduce the number of repeated admissions to the hospital, we may be able to improve the quality of their lives." Called the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure, the randomized, placebo-controlled multi-center trial will enroll approximately 1,000 patients at 80 sites nationwide, with about 24 patients being enrolled at UPMC Braddock.

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Researchers report novel ways to boost acceptance of transplants

Genetically altered dendritic cells (DCs) could significantly improve the body's acceptance of a transplanted organ, according to Pitt researchers in reports made at the 17th World Congress of the Transplantation Society held this summer.

Known as the pacemakers of the immune system, DCs are specialized white blood cells that regulate the activity of other immune cells within the body. In the case of organ transplantation, investigators are harnessing DCs to teach T cells to tolerate transplanted organs that would normally be recognized by the body as foreign. "DCs can be manipulated to disable the host's T cell response to a new organ," noted Angus Thomson, professor of surgery and director of transplant immunology at Pitt's Thomas E. Starzl Transplantation Institute.

One catch, however, is that donor dendritic cells transplanted together with an organ carry the same tissue markers that spur the host's immune system to reject a new graft. In effect, they could suffer rejection similar to a new organ, according to Thomson. In an animal transplant model, Pitt researchers circumvented this potential snag by genetically modifying donor-derived dendritic cells to churn out their own local supply of immunosuppressants. "The benefits are two-fold," Thomson explained. "First, by producing their own localized immunosuppressant, dendritic cells buy enough time to teach host T cells not to attack and 'evict' the new organ, as it were. Second, the immunosuppressants also dampen the attack of T cells on the new organ. And because these dendritic cells produce immunosuppressants at a local, rather than systemic level, this engineered process minimizes side effects such as infection associated with systemic delivery of immunosuppressants."

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Researchers build virtual aneurysms to aid in repairs

UPMC Health System researchers are using CT scans and computer modeling to construct "virtual aneurysms" which may aid surgeons in determining when to operate on an abdominal aortic aneurysm (AAA) before it ruptures.

Some 15,000 Americans die each year from AAAs, which are a ballooning or bulging of the aorta, the main artery that carries blood to organs and lower extremities. Left untreated, the aneurysm will expand until it ruptures, causing death in up to 80 percent of patients.

"We are combining medical imaging techniques with engineering analyses to develop a non-invasive method of estimating AAA severity," said David Vorp, assistant professor of surgery and mechanical engineering and director of Pitt's Vascular Biomechanics and Vascular Research Lab. "By utilizing these models and estimating biomechanical stresses within the aneurysm wall, clinicians may be better able to assess a specific aneurysm's propensity to rupture and make a sound judgment on whether surgical intervention is warranted. Ideally, surgery is performed only when the associated risks are exceeded by the risk of an AAA rupture. Making this decision is presently very difficult since AAAs afflict mainly those over 60 years of age." The standard surgical procedure to repair an AAA involves a large abdominal incision. The aneurysm is repaired by suturing a Teflon/polyester graft into place inside the AAA. Recently, vascular surgeons at UPMC have used a minimally invasive procedure called endovascular surgery in which the aneurysm is repaired from inside the aorta using a catheter. The catheter contains a collapsed polyester tube which is inserted into the patient's femoral artery and moved to the site of the aneurysm. Once inside the aneurysm, a spring-type attachment system hooks the tube to the inside walls of the artery on either end of the aneurysm and is anchored into place. Blood then flows through the implant, depressurizing the aneurysm.

Endovascular surgery is still an exploratory field and only a small percentage of patients are eligible for this technique. Therefore, the only option for most patients is traditional surgical repair, according to Vorp.

"The decision to repair an aneurysm is usually based on its maximum diameter," he said. "Surgeons typically will repair an AAA when it exceeds 5 cm (2.5 inches) in diameter but this does not take into account important characteristics of individual aneurysms. Some AAAs may have the same maximum diameter, but may have differences in shape, wall thickness, or mechanical properties which could have an effect on their growth and potential to rupture.

"From an engineering perspective, the proper definition of 'critical state' for an AAA is when its capacity to withstand forces is about to be breached," Vorp said. "That is, a more sound indicator of the severity of a specific aneurysm is to compare the acting wall stresses to the tensile strength of the wall tissue, since AAA rupture occurs when the wall stresses exceed the strength." Vorp and his team have developed a technique to noninvasively assess the wall stresses acting in individual AAAs based on the patient's blood pressure and the virtual AAA, a three-dimensional reconstruction of CT scans taken prior to surgery. The scans provide cross-sectional images of the AAA which are then processed and refined by computer analyses into a virtual aneurysm.

Also in his research, Vorp has tested the tensile strength of 150 tissue samples taken at the time of AAA surgery repair and found a 50 percent decrease in the strength of the AAA wall compared to healthy aorta tissue.

"Our next step is to develop a method to noninvasively determine the tensile strength of an individual aneurysm, rather than a patient population, perhaps based on clinical parameters such as the patient's age, gender, body size, etc.," Vorp said. "Once this becomes a possibility, we may move this technology to the clinical setting. With the ability to estimate both wall stress and wall strength for an individual patient, we no longer would need to rely on a general rule of thumb to help guide the surgical decision for AAA patients. Instead, the decision of whether to surgically intervene may be customized for each particular patient based on his or her aneurysm." Additional information on Vorp's research is available at his Web site: //www.pitt.edu/~vorp.

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Study of blood substitute in trauma victims is canceled

UPMC Health System was one of about 40 sites nationwide that was asked to determine the effectiveness of a patented, experimental blood substitute in treating trauma victims with severe blood loss. The blood substitute, developed by Baxter Healthcare Corp., was used in emergency treatment along with standard therapy, including blood transfusion.

Recently, Baxter terminated the study, which had enrolled about 100 of its expected 850 participants from Oct. 1-Dec. 22, 1997, at 16 U.S. sites. An interim review by the study's independent data monitoring committee found that patients in the study treatment group had significantly higher mortality rates than those in the control group.

Although the data don't yet indicate why the treatment group had a higher death rate, Baxter canceled the study. Further data analysis is ongoing.

Pitt surgery professor Andrew Peitzman is principal investigator of the UPMC study.

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New biological markers may be indicator of prognosis in head & neck cancer patients

Findings that tissue levels of two proteins correlate closely with the prognosis of head and neck cancer may significantly alter the detection, staging and treatment of this disease, according to an article in the Journal of the National Cancer Institute.

The preliminary study, reported by researchers at the University of Pittsburgh Cancer Institute (UPCI), focuses on two proteins that accelerate the growth of cancer cells and now appear to predict clinical outcome as accurately as removing lymph nodes from the neck, the traditional method. UPCI's report also bolsters the theory that blocking overproduction of these two proteins might cure head and neck cancer.

The marker proteins — transforming growth factor alpha and its receptor, epidermal growth factor receptor — are known to be overproduced in breast, lung and ovarian cancers. Higher levels of the two proteins correlate with a worse prognosis; lower levels correlate with longer life expectancy.

Previous scientific reports have found that the proteins are not expressed uniformly within a specific type of cancer. Moreover, until now, no substantial support existed that levels of these proteins rival other traditional methods of measuring disease progression.

"Our findings have enormous potential. We could use this information to identify patients at high risk for recurrent disease and develop a targeted therapy based on the biology of these markers," said principal investigator Jennifer Rubin Grandis, director of UPCI's Head and Neck Cancer Program and a Pitt assistant professor of otolaryngology.

Head and neck cancer strikes more than 30,000 people in the United States annually, and is difficult to treat. Risk factors include smoking and drinking alcohol.