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June 10, 2010

Research Notes

Hepatic melanoma treatment tested

Patients undergoing treatment for melanoma that has spread to the liver may respond well to chemotherapy delivered directly into the liver’s blood vessels, according to a study led by Pitt surgery department faculty member and UPMC Cancer Centers surgical oncologist James F. Pingpank. The results were presented recently at the annual meeting of the American Society of Clinical Oncology.

“Once melanoma spreads to the liver, a patient’s life expectancy typically ranges from six to nine months,” said Pingpank. “We hoped this study would not only show an increase in progression-free survival rates for these patients, but also lead to a standard of care for the disease.”

The phase III trial enrolled 93 patients from 10 different sites across the country. Its primary goal was to double the length of hepatic progression-free survival for patients with melanoma that had spread to the liver. Patients received either percutaneous hepatic perfusion (PHP) with the drug melphalan, meaning the chemotherapy was delivered directly into the blood vessels of the liver, or the treatment considered the best alternative regimen by their treating physician. If a patient not receiving PHP had disease progression, he or she could cross over to the PHP arm of the trial.

“Not only did we achieve our goal, we surpassed it,” said Pingpank. “PHP appears to control tumors in the liver and extend life expectancy for these patients, whether their melanoma began as skin cancer or as ocular melanoma. Fifty percent of ocular melanoma patients will experience liver metastasis, so these findings are crucial for them.”

Cancer targeted via ATM kinase

Researchers at the University of Pittsburgh Cancer Institute (UPCI) and the School of Medicine have discovered that inhibiting a key molecule in a DNA repair pathway could provide the means to make cancer cells more sensitive to radiation therapy while protecting healthy cells.

Senior author Chris Bakkenist, a faculty member in radiation oncology, pharmacology and chemical biology, said the findings provide new insights into mechanisms of how the body fixes environmentally induced DNA damage and into the deadly neurological disease ataxia-telangiectasia (A-T). The results were published in Science Signaling.

“A characteristic symptom of A-T is heightened sensitivity to ionizing radiation, such as X-rays and gamma rays,” he said. “If we understand why that happens, then we might be able to reproduce it to make tumor cells vulnerable to radiation treatments while sparing healthy cells, which would make therapy more effective while minimizing side effects.”

In A-T, brain areas that control movement progressively degenerate, causing walking and balance problems. Patients carry a gene mutation that stops production of a protein called ATM kinase, which spurs other proteins involved in normal cell division, DNA repair and cell death.

Radiation causes DNA mutations during the process of cell division, when genetic material is copied for a new cell to form. The cell has repair pathways that include checkpoints to look for errors as well as methods to repair them, but if enough mutations accumulate, the cell could become cancerous or self-destruct. A-T patients, who lack the kinase, have a higher risk for developing cancer, Bakkenist said.

He and his colleagues tested what would happen if they blocked the activity of ATM kinase in cells that make the protein. They already had determined that administering an ATM kinase inhibitor 15-75 minutes after radiation exposure was sufficient to make normal cells more sensitive to the effects of radiation.

To their surprise, they found that inactivation of ATM kinase prevented a type of DNA repair that is essential for proper duplication of genetic material during replication. However, A-T cells did not have this problem despite lacking the kinase; they presumably use another method to check for and correct those errors.

The discovery revealed a new approach to targeting cancer.

“A characteristic of tumor cells is that they rapidly replicate, possibly because they have mutations that encourage cell division or that thwart repair pathways,” Bakkenist explained. “But ATM kinase remains present in the vast majority of human cancers, so that suggests it is needed by those diseased cells during replication.”

Cells that, unlike cancer cells, are not going through what is known as replication stress, would not be affected by an ATM inhibitor and, like A-T cells, probably have another way of repairing certain radiation-induced mutations, he said.

“So that would make cancer cells particularly vulnerable to an ATM inhibitor, while healthy cells should be unaffected,” Bakkenist said.

Among the co-authors of the paper was Serah Choi of radiation oncology.

Anti-seizure drug may undo liver damage

The liver scarring of alpha 1-antitrypsin (AT) deficiency, the most common genetic cause for which children undergo liver transplantation, might be reversed or prevented with a medication that long has been used to treat seizures, according to findings published in Science and online in Science Express by researchers in the School of Medicine and Children’s Hospital.

Because the anti-seizure drug is familiar to doctors and has a well-understood safety profile, clinical trials could begin immediately to see whether it can help patients with AT deficiency, said senior author David H. Perlmutter, Vira I. Heinz Professor and chair of the medical school’s Department of Pediatrics and physician-in-chief and scientific director at Children’s Hospital.

In the classic form of the disease, which affects 1 in 3,000 live births, a gene mutation leads to an abnormal protein, ATZ, which, unlike its normal counterpart, is prone to aggregation.

“These aggregates of ATZ accumulate in the liver cells and eventually lead to scarring, or fibrosis, of the organ and set the stage for tumor development,” Perlmutter said. “The disease sometimes doesn’t show itself until adulthood, when the liver starts to fail due to cirrhosis or cancer.”

For the study, he and his colleagues treated an ATZ cell line with carbamazepine, or Tegretol. Although this drug has been used primarily to treat seizure disorders, some recent work has suggested that it could enhance a natural cellular pathway called autophagy, or self-digestion, and so the Pitt researchers reasoned that it might be able to rid the cells of the toxic aggregated ATZ.

They found that carbamazepine did cause a marked decrease in ATZ because the abnormal proteins were degraded more quickly via autophagy, so they did another experiment in a mouse model of AT deficiency.

“The amount of ATZ decreased in the livers of the mice treated with carbamazepine,” Perlmutter said. “The most amazing finding was that the drug reversed the fibrosis in the livers of the mice and, after two weeks of treatment, the liver tissue resembled that of a healthy mouse.”

The ability of carbamazepine and similar drugs to aid auto-phagy might have value in other disorders such as Alzheimer’s, Huntington’s and Parkinsonism, which are thought to be caused by toxic effects of protein clumping in the brain.

Perlmutter and his colleagues are exploring these possibilities in preclinical studies.

The team included lead author Tunda Hidvegi, pediatrics; Simon C. Watkins, cell biology and physiology, and George Michalopoulos, pathology.

Differentiation of cancer stem cells halted

Scientists from Children’s Hospital and the School of Medicine have found a way of blocking cancer stem cells from differentiating into other types of tumor-forming cells.

The discovery, published in the June issue of the journal Stem Cells, will allow researchers to further study and characterize cancer stem cells and to screen drugs that could target them specifically.

Although they make up a relatively small portion of a tumor, cancer stem cells are believed to initiate and sustain tumors as they grow and metastasize. Cancer stem cells differentiate into other cells within three-five weeks of being isolated, making them difficult to study, according to Edward Prochownik, the Paul C. Gaffney Professor of Pediatrics and professor of molecular genetics and biochemistry at the School of Medicine and director of oncology research at Children’s Hospital.

Prochownik and his colleagues were able to isolate and tag four lines of breast cancer stem cells with green fluorescent protein and a stem cell-specific promoter know as Oct3/4.

“Using this approach, we can essentially freeze the stem cells in their current state, grow them in unlimited quantities and then study them at our leisure so we’ll be able to understand what makes cancer stem cells more efficient than other types of cancer cells,” Prochownik said.

“More importantly, having this unlimited supply of cancer stem cells allows us to use existing technology to screen them for chemotherapy agents and other therapies to determine which therapies are most effective at destroying the cancer stem cells. The goal is an arsenal of therapies to target both the tumor as a whole as well as those specific to the cancer stem cells.”

The discovery of how to block these cancer stem cells was serendipitous; Prochownik and his team initially were trying to develop a way to track the cancer stem cells to determine what other types of cells they differentiated into and how long the process takes.

Prochownik’s team at the hospital’s Rangos Research Center now is studying whether their method of blocking breast cancer stem cells also blocks those from other types of tumors. They also are screening large numbers of drugs to identify new ones that may be more effective against breast cancer stem cells.

Other Pitt study authors included Fang Zhang, pharmacology and chemical biology; David J. Dabbs, pathology, and Stephen G. Grant, environmental and occupational health.

Lymphedema mutation found

A genetic mutation for inherited lymphedema associated with lymphatic function has been discovered that could help create new treatments for the condition, say researchers at the Graduate School of Public Health (GSPH). Their findings were reported in the June issue of the American Journal of Human Genetics.

Lymphedema, the swelling of body tissues caused by an accumulation of fluid in a blocked or damaged lymphatic system, affects more than 120 million people worldwide. The most common treatments are a combination of massage, compression garments and bandaging.

David N. Finegold, co-principal investigator of the study and faculty member in human genetics, said: “Most people with inherited lymphedema suffer their entire lives with treatments that address symptom relief only. There is no drug available to cure or even treat it.”

Pitt’s lymphedema family study began collecting data from affected families in 1995 to learn more about the risk factors and causes of inherited, or primary, lymphedema.Research has helped identify six genes linked to the development of lymphedema, but until now researchers had no insight into the genetic factors responsible for lymphatic vascular abnormalities.

In their study, Finegold and colleagues sequenced three genes expressed in families with primary lymphedema. Mutations in one of these genes, GJC2, was found in primary lymphedema families and are likely to impair the ability of cells to push fluid throughout the lymphatic system by interrupting their signaling. Without proper signaling, cell contraction necessary for the movement of fluid did not occur, leading to its accumulation in soft body tissues.

“These results are significant because they give us insight into the cell mechanics that may underlie this condition,” said Finegold. “With further research, we may be able to target this gene with drugs and improve its function.”

Pitt co-authors included Robert E. Ferrell, Mark A. Kimak, Elizabeth C. Lawrence and Eleanor Feingold of human genetics; Catherine J. Baty and Jenny M. Karlsson of cell biology and physiology, and Stephen D. Meriney of neuroscience.

DoD awards McGowan $12M for human trials

The McGowan Institute for Regenerative Medicine has been awarded a two-year, $12 million contract with the U.S. Department of Defense Office of Technology Transition (OTT) that will jumpstart human trials in three research programs that aim to replace scars and defects with healthy, functional tissues.

The OTT mission emphasizes the rapid translation of preclinical research into human studies to bring successful therapies more quickly to everyday practice, said Alan Russell, director of the McGowan Institute and leader of the new program.

“This initiative provides fiscal support and also represents a shared commitment to the goal of helping soldiers return to the lives they have put on the line for us,” he said.

The OTT initiative will focus on efforts to:

Replace muscle tissue through extracellular matrix, a protein- and growth factor-rich biological scaffold that appears to recruit stem cells and other precursors to injury sites. Primary investigators are Stephen Badylak, deputy director of the McGowan Institute, and J. Peter Rubin of the School of Medicine  Department of Surgery.

Bring to clinical testing an injectable, porous bone cement for the repair of craniofacial bone defects and restoration of normal bone growth and remodeling. Primary investigators are Bernard J. Costello and Charles Sfeir,  School of Dental Medicine, and Prashant N. Kumta, the Edward R. Weidlein Chair in the Swanson School of Engineering’s Department of Mechanical Engineering and Materials Science.

• Evaluate the injection of human fibroblasts, a type of connective tissue cell, into contracted burn scars to soften the skin and allow greater freedom of movement. Rubin is co-primary investigator.

The OTT initiative is funded by the Joint Improvised Explosive Device Defeat Organization. The projects ultimately could lead to interventions that also benefit civilians.

Microbicides research presented

Pitt researchers were among the presenters at the International Microbicides Conference.

Lube safety evaluated

A laboratory study that compared over-the-counter and mail-order lubricants commonly used with receptive anal intercourse found many had toxic effects on cells.

Some of the lubricants caused significant portions of the epithelium — the layer of cells that serves as a protective barrier inside the rectum — to be stripped away.

Conclusions cannot be made based on this study alone, but the results are compelling enough to wonder if these lubricants might have the same effect in people and thereby increase susceptibility to HIV, commented Charlene Dezzutti of the Department of Obstetrics, Gynecology and Reproductive Sciences, the Department of Molecular Genetics and Biochemistry and Magee-Womens Research Institute, who led the study for the Microbicide Trials Network.

Five products (Astroglide, Elbow Grease, ID Glide, KY Jelly and Wet Platinum) were selected because they had been identified as those most commonly used by more than 6,300 respondents to an International Rectal Microbicide Advocates survey. A sixth product (PRÉ) was selected to serve as a control because it has the same concentration of dissolved salts and sugars as is found inside cells. (Products with a higher concentration of salts and sugars cause cells to force water out to correct the imbalance, after which they wither and die.)

Based on the tests performed to determine the effect of each lubricant on rectal and cervical tissue and on bacteria important to the health of the rectum, PRÉ and Wet Platinum were shown to be safest, while Astroglide was the most toxic to cells and tissues. KY Jelly had the worst effect on the good bacteria, essentially wiping out an entire colony. PRÉ was the only water-based lubricant that did not disrupt the epithelium.

None of the lubricants had measurable anti-HIV activity. In future studies, the researchers hope to determine the effect that different lubricants have on susceptibility to HIV infection in tissues.

Other Pitt investigators included Lisa C. Rohan of pharmaceutical science and Bernard Moncla of obstetrics, gynecology and reproductive sciences.

Microbicide gel use in pregnancy tested

Results of the first study of a vaginal microbicide tested in pregnant women found only small amounts of the drug are absorbed into the mother’s blood, amniotic fluid and umbilical cord blood.

The study, which involved applying a single dose of tenofovir gel hours before women gave birth by Caesarean delivery, was conducted as a first step toward determining if use of a vaginal microbicide during pregnancy is safe for women and their babies.

The findings support continuing with further studies of tenofovir gel in pregnant women, said Richard Beigi, a faculty member in the Department of Obstetrics, Gynecology and Reproductive Sciences, who led the study for the Microbicide Trials Network.

The active ingredient in tenofovir gel is an antiretroviral that is approved as an oral drug and used as part of the standard HIV treatment regimen. Both research and clinical experience with the oral drug have indicated its use is safe in HIV-infected women during pregnancy.

In previous studies looking at the use of oral tenofovir for the prevention of mother-to-child transmission of HIV, researchers found that low amounts of the drug pass to the baby.

In the current trial, which involved healthy, uninfected pregnant women, the amount of drug found in umbilical cord blood was 40 times lower than cord blood levels noted in these other studies after oral dosing, and the amount that got absorbed into the maternal blood was at levels 50-100 times lower.

UPB survey hopes to foster entrepreneurs

Researchers from Pitt-Bradford’s entrepreneurship program and the Center for Rural Entrepreneurship have surveyed local youth with the hope of fostering future entrepreneurs.

The survey asked 1,782 students in grades 7-12 about their activities, plans and whether they would like to continue living in the area.

Thirty-six percent of students said they were interested in owning a business in the future. The kinds of businesses cited included a veterinary clinic, retail stores, media outlets, manufacturing plants and tourist destinations, such as an indoor baseball facility.

Ten percent said they already own a business, such as a babysitting or lawn-mowing business, a family-owned machine shop, a web site and a glass company.

Laura Megill, director of the Pitt-Bradford entrepreneurship program, presented the results to focus groups and said the students had a more positive view of their hometown than many adults.

Forty-five percent of students said they could picture themselves living in the area. Of those who saw themselves returning to Warren County, 78 percent said it was a good place to raise a family. Of those who did not see themselves returning, most said they could make more money or have better career opportunities elsewhere.

Megill hopes that those who work with youth in the county can use the survey as a tool to support entrepreneurial endeavors and education for young people.

Diving deeper into turbulence

When a fluid flows along a boundary, irregularities in the boundary surface cause frictional drag, which in turn creates turbulence. The effects of turbulence govern the flow of rivers and oil pipelines, the drag on airplanes and baseballs and even the circulation of blood.

Despite its importance, however, turbulence is not well understood. Even today, engineers cannot predict accurately the pressure needed to force a fluid such as oil or natural gas through a pipeline at a desired rate; instead they infer flow rates from charts based on 1930s phenomenological experiments.

The long-sought connection between frictional drag and the eddies in fluid flow, first predicted theoretically by University of Illinois researchers, has been established experimentally as reported recently in a Nature Physics cover article.

The measurements were performed by a team from the University of Illinois-Urbana/Champaign; also contributing to the research were Pitt professor emeritus of physics and astronomy Walter Goldburg and his student Alisia Prescott, as well as researchers from the University of Bordeaux.

In these experiments, a vertically flowing soap film held between two wires is pierced by a turbulence-inducing comb and the fluid motion probed by laser beams. The soap film is thin enough that the fluid behaves as if it were two-dimensional, not three-dimensional.

The setup measures both the two-dimensional turbulent velocity fluctuations and the frictional drag at the bounding wires.

Because of the relationship between the fluctuations and the drag, the theory predicts that in two-dimensional fluids, the drag should have a special dependence on the flow speed, different from that observed in regular three-dimensional turbulent pipe flow.

The new experiments fully support the Illinois theoretical work, but are inconsistent with the standard textbook expectations that date back to the 1930s.

Although turbulence remains a challenging problem, progress has occurred because the investigators asked a new question: How can we connect the small-scale fluctuations in the turbulent fluid to the large-scale effects of turbulent drag?

According to the team, the implications of the work have practical applications such as in predicting how to transport oil and gas through long pipelines at lower energy costs by adding polymer molecules to the fluid to make it flow with less drag.

Sorafenib no help against melanoma

The combination of two different chemotherapies and a previously approved treatment for kidney and liver cancers is not effective against advanced melanoma, according to results presented at the annual meeting of the American Society of Clinical Oncology.

Pitt professor of medicine John M. Kirkwood, leader of the University of Pittsburgh Cancer Institute’s melanoma and skin cancer program, said: “With this study, we learned that the addition of sorafenib, a molecular inhibitor, to a traditional chemotherapy regimen does not improve patient survival.”

The phase III trial enrolled 823 patients from seven different sites over 34 months to determine whether the addition of sorafenib, a molecular targeting agent, would improve survival rates for patients with metastatic melanoma when added to the chemotherapy combination of carboplatin and paclitaxel. Patients either received the chemotherapy combination alone or with sorafenib.

“While this study didn’t confirm the very promising results of phase II studies with sorafenib, it is important to share its findings since the double chemotherapy combination of carboplatin and paclitaxel has achieved results that eclipse previous chemotherapy results in large phase III trials. These results take us one step closer to understanding how to most effectively treat metastatic melanoma,” said Kirkwood. 

Prof develops method to clean up oil spills

In response to the massive oil leak in the Gulf of Mexico, a Pitt engineering professor has developed a technique for separating oil from water via a cotton filter coated in a chemical polymer that blocks oil while allowing water to pass through.

Di Gao reports that the filter was tested off the coast of Louisiana and shown to simultaneously clean water and preserve the oil.

Gao, faculty member and William Kepler Whiteford Faculty Fellow in the Department of Chemical and Petroleum Engineering in the Swanson School of Engineering, created his filter as a possible method to help manage the spreading oil slick that resulted from the April 20 explosion of BP’s Deepwater Horizon drilling platform. Gao has submitted his idea through the Deepwater Horizon response web site managed by the consortium of companies and government agencies overseeing the disaster response.

A video of Gao testing his filter with oil and water samples from the Gulf of Mexico spill is available on YouTube at

Gao’s filter hinges on a polymer that is both hydrophilic — it bonds with the hydrogen molecules in water —and oleophobic, meaning that it repels oil. When the polymer is applied to an ordinary cotton filter, it allows water to pass through but not oil. The filter is produced by submerging the cotton in a liquid solution containing the polymer, then drying it, Gao explained.

For the massive slick off the U.S. Gulf Coast, Gao envisions large, trough-shaped filters that could be dragged through the water to capture surface oil. The oil could be recovered and stored and the filter reused. Current cleanup methods range from giant containment booms and absorbent skimmers to controlled fires and chemical dispersants with questionable effects on human health and the environment.

Gao focuses his research in the development and application of chemical nanostructures, including liquid-resistant coatings. In 2009, Gao reported in the journal Langmuir his demonstration of a nanoparticle-based solution that can prevent the formation of ice on solid surfaces, from power lines to airport runways and roads.


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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