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March 19, 2015

Research Notes

Healing cirrhotic liver disease could be possible

It might be possible to heal cirrhotic liver disease by rebooting the genes that control liver cell function, according to researchers at the School of Medicine and Children’s Hospital of Pittsburgh of UPMC. If validated in human studies, the game-changing strategy, described online in the Journal of Clinical Investigation, potentially could treat patients who are too sick for liver transplantation and someday reduce the need for transplants.

The project grew out of the observation that not everyone who develops cirrhosis, or scarring of the liver, progresses to liver failure and its life-threatening complications.

Said Ira Fox, professor of surgery in the school and director of the Center for Innovative Regenerative Therapies at Children’s Hospital and the McGowan Institute for Regenerative Medicine: “Even with the large amount of scar tissue that comes with cirrhosis, there should be enough cells left to carry out the normal functions of the liver. So when the liver fails, it is the liver cells themselves that aren’t working properly. In this study, we demonstrate what has caused the problem and, more importantly, a way to repair it.”

His team developed a rat model of liver disease that mimics the form of human cirrhosis that progresses to organ failure. In previous work, they found that liver cells taken from animals with cirrhosis but no liver failure immediately functioned properly when transplanted into another animal. But cells transplanted from animals with both cirrhosis and liver failure did not function normally at first, indicating that both the liver cells and the liver tissue environment were damaged.

The researchers then compared the genes in the liver cells of the two groups of cirrhotic rats and found unusually low activity levels of the genes controlling proteins that play a central role in liver cell function, the most important being a factor called HNF4.

In the new paper, they showed that restoring production of HNF4 by gene therapy reboots the liver cells to normal function. The team first showed this in lab tests and then in rats with liver failure.

“We were pleased to see that the animals got better almost immediately. Remarkably, our tests indicated that it wasn’t stem cells, regeneration or growth of new liver cells that caused improvement. Instead, the diseased cells had healed,” Fox said.

HNF4 gene therapy provided unique insight into the cause of liver failure and has significant potential for human therapy, but the investigators now are looking for other gene targets to develop simpler therapies, such as drugs that block the pathways that mediate failure. The team also is confirming its results with human liver cells.

Pitt co-investigators include Alejandro Soto-Gutierrez, Joseph Locker and others from medicine, Children’s Hospital and the McGowan Institute. Researchers from Penn and Kyoto Prefectural University of Medicine in Japan also contributed.

The project was funded by the National Institutes of Health (NIH) and the Department of Defense.

Why behavior changes as material gets smaller

To fully understand how nanomaterials behave, one also must understand the atomic-scale deformation mechanisms that determine their structure and, therefore, their strength and function.

Researchers at the Swanson School of Engineering, Drexel and Georgia Tech have engineered a new way to observe and study these mechanisms and, in doing so, have revealed an interesting phenomenon in a well-known material, tungsten. The group is the first to observe atomic-level deformation twinning in body-centered cubic (BCC) tungsten nanocrystals.

The team used a high-resolution transmission electron microscope (TEM) and sophisticated computer modeling to make the observation. This work, published in Nature Materials, represents a milestone in the in-situ study of mechanical behaviors of nanomaterials.

Deformation twinning, in conjunction with dislocation slip, allows materials to permanently deform without breaking. In the process of twinning, the crystal reorients, which creates a region in the crystal that is a mirror image of the original crystal. Twinning has been observed in large-scale BCC metals and alloys during deformation. However, whether twinning occurs in BCC nanomaterials remained unknown.

Said Scott X. Mao, the paper’s senior author and Swanson faculty member in mechanical engineering and materials science: “To gain a deep understanding of deformation in BCC nanomaterials, we combined atomic-scale imaging and simulations to show that twinning activities dominated for most loading conditions due to the lack of other shear deformation mechanisms in nanoscale BCC lattices.”

The team chose tungsten as a typical BCC crystal. The most familiar application of tungsten is its use as filaments for light bulbs.

The observation of atomic-scale twinning was made inside a TEM. This kind of study had not been possible in the past due to difficulties in making BCC samples less than 100 nanometers in size as required by TEM imaging. Jiangwei Wang, a Swanson school graduate student in mechanical and industrial engineering and lead author of the paper, developed a way of making the BCC tungsten nanowires. Under a TEM, Wang welded together two small pieces of individual nanoscale tungsten crystals to create a wire about 20 nanometers in diameter. This wire was durable enough to stretch and compress while Wang observed the twinning phenomenon in real time.

To better understand the phenomenon observed by Mao and Wang’s team at Pitt, a Drexel researcher developed computer models that show the mechanical behavior of the tungsten nanostructure at the atomic level. This modeling allowed the team to see the physical factors at play during twinning. This information will help researchers theorize why it occurs in nanoscale tungsten and plot a course for examining this behavior in other BCC materials.

Georgia Tech researchers conducted advanced computer simulations using molecular dynamics to study deformation processes in 3-D.

The twinning mechanism, said Mao, contrasts with the conventional wisdom of dislocation nucleation-controlled plasticity in nanomaterials. The results should motivate further experimental and modeling investigation of deformation mechanisms in nanoscale metals and alloys, ultimately enabling the design of nanostructured materials to fully realize their latent mechanical strength.

Workplace lifestyle intervention program improves health

A workplace-based healthy lifestyle intervention program developed by the Graduate School of Public Health significantly reduces risk factors for diabetes and heart disease, according to a study reported in the Journal of Occupational and Environmental Medicine.

The program was well-received by participants at Bayer Corp., who lost weight and increased the amount of physical activity they got each day, when compared with a control group in the study.

Said lead author M. Kaye Kramer, public health faculty member in the Department of Epidemiology and director of the school’s Diabetes Prevention Support Center: “Health care expenditures associated with diabetes are spiraling, causing widespread concern, particularly for employers who worry about employee health and productivity. This leads to an interest in workplace health promotion. However, there are very few evidence-based programs that actually demonstrate improvement in employee health. This study found that our program not only improves health, but also that employees really like it.”

This demonstration program is based on the U.S. Diabetes Prevention Program (DPP), a national study that found people at risk for diabetes who lost a modest amount of weight through diet and exercise sharply reduced their chances of developing diabetes, outperforming people who took a diabetes drug instead.

Kramer and colleagues built on the DPP to create the Group Lifestyle Balance program that puts the findings into practice. The program is divided into 22 sessions over a one-year period and aimed at helping people make lifestyle changes to improve health. The sessions can be done as a group with a lifestyle coach or through a DVD coupled with brief weekly phone or email consultations with the lifestyle coach. The option of the DVD with lifestyle coach support not only served as the main intervention option for those employees who traveled or who did not want to participate in the program in a group venue, but also offered a replacement for employees who chose to participate via group setting but had to miss an occasional session.

Said senior author Andrea Kriska, an epidemiology faculty member and principal investigator of the study: “Our Group Lifestyle Balance program has proven successful in diverse community settings, so we adapted it for the workplace since we found that there was a real need for effective programs that could fit into people’s work lives. This current effort in the worksite shows clearly that a proven healthy lifestyle program, like the Group Lifestyle Balance program, offered to people where they work is not only feasible but effective in reducing risk factors for diabetes and heart disease for participating employees.”

A total of 89 employees at Bayer Corp. in Robinson who were at risk for diabetes or heart disease were enrolled in the demonstration program in 2010 and followed for 18 months.

Over the course of a year, participants lost an average of 5 percent of their body weight (10 pounds), shrunk their waistlines by about 2 inches and brought down the levels of fat and sugar in their blood — all measures that reduce the risk of heart disease and diabetes. They nearly doubled their physical activity.

Of the participants, 96 percent said they felt it was beneficial to offer the program at the worksite, and 99 percent said they would recommend it to their coworkers.

Additional Pitt researchers included Elizabeth Venditti, Vincent C. Arena, Rebecca Meehan, Rachel Miller, Karl Vanderwood and Yvonne Eaglehouse, with a colleague from the Veterans Health Administration in Minneapolis.

This research was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases of the NIH.

Early onset of hot flashes could predict heart disease

Women who experience hot flashes early in menopause are more likely to have markers of blood vessel dysfunction, which could indicate a higher risk for the development of heart disease, according to a Pitt researcher. Findings were presented at the American College of Cardiology’s annual scientific session and expo.

Up to 70 percent of women experience hot flashes and night sweats during menopause.

Said Rebecca Thurston of psychiatry: “We used to think these were just annoying symptoms that many women just tried to endure. However, our research is now suggesting that for some women, hot flashes might indicate adverse changes in the blood vessels during midlife that might not be medically benign over time.”

Preliminary findings from Thurston’s research indicate that early onset of hot flashes is associated with dysfunction of the endothelium, which is the lining of blood vessels. Endothelial dysfunction was measured by assessing flow-mediated dilation (FMD), a noninvasive ultrasound gauge of how well the vessel dilates in response to pressure on the wall of the blood vessel.

In one study of 189 healthy women approaching or in menopause, the researchers found those who had hot flashes before age 52 were more likely to have lower FMD values, suggesting adverse endothelial changes. Similarly, in a second study of 104 postmenopausal women with signs of heart disease, those who reported first having their hot flashes at or before age 42 were more likely to have lower FMD values.

“More work needs to be done to confirm our findings and to understand the reasons why early hot flashes are associated with endothelial dysfunction,” Thurston said. “But these findings could give us a way to predict who might be at greater risk for heart disease so that we can target these women for early prevention.”

Ancient Mongol metallurgy an extreme polluter

The ancient Mongols have a reputation for having been fierce warriors. A new study out of the Department of Geology and Planetary Science in the Dietrich School of Arts and Sciences shows them to have been unmatched polluters.

Graduate student Aubrey Hillman’s study in the journal Environmental Science & Technology shows copper and silver production in southwest China produced tremendous quantities of harmful heavy metals, such as lead, silver, zinc and cadmium, starting in 1500 BC and continuing through the era of the Mongol Yuan Dynasty (1271-1368 AD). Hillman worked under her adviser and department chair Mark Abbott.

In 2009, Hillman and colleagues took core samples from Lake Erhai in the Yunnan province in southwestern China. The site was chosen because of its proximity to Kublai Khan’s famed silver mines — Khan was the grandson of Genghis Khan and founder of the Yuan Dynasty — and the area where ancient bronze artifacts had been found.

The researchers found that lead pollution in Lake Erhai peaked at 119 micrograms per gram of sediment in 1300 AD before declining to around 30 micrograms per gram in 1420 AD. Peak pollution levels were three to four times higher than those generated by modern metallurgical methods, Hillman says.

“Notably, the concentrations of lead approach levels at which harmful effects may be observed in aquatic organisms,” Hillman noted. “The persistence of this lead pollution over time created an environmental legacy that likely contributes to known issues in modern-day sediment quality.

“We went back in 2012 to confirm how widespread the pollution was,” she continued. “Many studies have documented lead and metal pollution from early metalworking, but this study is the first to show that pollution was greater in the past than today.”

And her findings, she said, may have practical use today: “The (metallurgic) processes would have volatilized heavy metals and spread throughout the landscape,” not just Lake Erhai, which could have implications for agriculture since, as recent reports suggest, as much as one-sixth of China’s arable land is affected by excessive accumulation of heavy metals.

Women requesting PFA orders see decreased earnings

“Why doesn’t she just leave?” is a timeworn question about women in relationships that are physically and/or emotionally abusive to them. Economic dependence clearly is part of the story — many women lack the financial means to leave and find themselves trapped by both poverty and abuse.

Of the women who do attempt to escape the abuse, some opt to petition a judge for a civil restraining order, also called a Protection From Abuse (PFA) order, for protection from abuse, harassment, threats or intimidation. Research shows that PFAs can promote women’s safety and help women manage the threat of abuse.

However, a new study shows that turning to the courts may not be effective at helping these women earn more money or even return to their prior level of earnings growth.

Sociology faculty members Lisa Brush and Melanie Hughes in the Dietrich School and Arts and Sciences have coauthored “The Price of Protection: A Trajectory Analysis of Civil Remedies for Abuse and Women’s Earnings,” published in the American Sociological Review, a journal of the American Sociological Association.

The paper investigates changes in women’s earnings before and after they petition the courts for a restraining order against an abuser. Brush and Hughes found overwhelming evidence that this period of petitioning is accompanied by serious financial instability, vulnerability and hardship for women. In fact, the researchers estimate that women lose $312-$1,018 in the year after petitioning and are not recouping those losses.

The researchers believe their study is the first to assess what happens to women’s earnings before, during and after petitioning for a restraining order.

The researchers studied records of 3,923 women in Allegheny County who had reported any earnings between January 1995 and December 2000 and who had petitioned for a PFA order between January 1996 and December 1999. They looked for changes in earnings growth before and after petitioning. They also took into account whether the women were on welfare prior to or after petitioning, and whether they secured just the initial PFA of usually 10 days or followed through and requested a hearing, a necessary step for a long-term restraining order. (In Allegheny County, judges can grant petitioners a temporary 10-day restraining order and then a longer 12-18-month renewable order.)

Said Hughes: “Our study convincingly shows that women’s petitioning for a PFA does not come with either short- or long-term increases in earnings growth. We cannot offer women a restraining order as a tool to stop abuse and then walk away. We need to offer women other forms of support, especially economic ones, during this unstable time.”

The researchers say the study is just a first step toward unpacking the costs of women’s efforts to end abuse. They say the economic loss women experience when petitioning for a PFA is a call to researchers, advocates and policymakers to develop strategies to enhance women’s safety, solvency and economic stability.

Hormone-altering chemical in pregnancy influences sex development

Exposure to hormone-altering chemicals called phthalates —which are found in many plastics, foods and personal care products — early in pregnancy is associated with a disruption in an essential pregnancy hormone and adversely affects the masculinization of male genitals in the baby, according to research led by the Graduate School of Public Health.

The findings, presented at the Endocrine Society’s annual meeting, focus on the role of the placenta in responding to these chemicals and altering levels of a key pregnancy hormone. These results suggest that there may be reason to push routine clinical testing earlier in pregnancy to check for the effects of chemicals and help guide potential interventions to protect the health of the baby.

Said Jennifer Adibi, epidemiology faculty member: “Phthalates are pervasive. Reducing exposure to phthalates and other hormone-disrupting chemicals is something that needs to be addressed at a societal level through consumer advocacy and regulation, and education of health care providers.”

The research builds on a study led by the Icahn School of Medicine at Mount Sinai and published in the journal Human Reproduction. The current presentation provides new information about how phthalates target a key pregnancy hormone called human chorionic gonadotropin (hCG), which is made by the placenta and can be measured in the mother’s blood and urine.

“The placenta, which is an extension of the fetus and a target of the chemicals in our bodies, broadcasts information early in pregnancy, through hCG, about what might be occurring to the fetus from chemical exposure,” said Adibi. “A long-term benefit of this research might be the development of new knowledge and methods for earlier screening in pregnancy, with the potential to act on this information to improve the long-term health of the future child.”

Adibi and her colleagues analyzed data collected from approximately 350 women and their babies who participated in a multicenter investigation called The Infant Development and the Environment Study (TIDES). Between 2010 and 2012, the women gave blood and urine samples in their first trimester of pregnancy and allowed researchers to take measurements of the babies at birth.

Higher levels of two molecules that are produced when phthalates are digested — mono-n-butyl and monobenzyl phthalate — in the mothers’ urine early in pregnancy were significantly associated with lower levels of hCG in women carrying male babies and with higher hCG in those carrying female babies.

The new research also looked at hCG in relation to a biological marker called anogenital distance, which is the distance between the anus and genitals. In men, a short anogenital distance is associated with decreased sperm count and infertility.

Higher levels of hCG in the mother’s blood were associated with a shorter anogenital distance in male babies. The researchers estimate that about 20-30 percent of the phthalate effect on the babies’ genitals could be attributed to the influence of phthalates on hCG, specifically mono-n-butyl and mono-ethylhexyl phthalate.

“Our study is the first to look at hCG as a target of phthalate exposure in pregnancy,” said Adibi. “There is growing societal concern over pediatric disorders that have a basis in the fetal period and which may be more common in one sex or another, such as autism, attention deficit disorder, obesity, asthma and infertility. It is important to find out if chemicals in our food or environment might influence these conditions.”

The participants in this study were enrolled at prenatal clinics in California, Washington, Minnesota and New York. Adibi’s future studies will enroll women in the earliest stages of pregnancy at clinics in Pittsburgh to assess exposures to endocrine disruptors and measure effects on the placenta and the baby.

Additional researchers on this study were Myoung Keun Lee of Pitt and colleagues at McGill University, the University of Rochester, the University of Minnesota, the University of Washington and the University of California.

This research was funded by National Institutes of Environmental Health Sciences.

Supplemental oxygen can make tumors shrink

A method of profoundly enhancing some cancer treatments could be right under our noses. A study coauthored by a School of Medicine researcher has shown in an animal model that breathing air with a higher-than-usual concentration of oxygen can alter certain metabolic pathways to allow chemotherapy and immunotherapy to shrink tumors more effectively.

The blood supply of a tumor often does not match the pace of the cancer’s growth, which leads to areas that are ischemic, or oxygen deprived. That causes the tumor cells to make adenosine, a molecule that not only promotes blood flow, but also binds to a receptor on killer T-cells and essentially puts them to sleep. In effect, adenosine acts as a shield against immune system cells that otherwise would attack the cancer.

Said Edwin Jackson, pharmacology and chemical biology faculty member and a coauthor of a paper published online in Science Translational Medicine: “We realized if we could find a way to block the increase in adenosine, we might be able to help the immune system respond to the tumor to make anticancer therapies more effective. This study shows that simply breathing more oxygen can accomplish that aim, which could lead to an amazing breakthrough in cancer treatment.”

The study team, led by a colleague from the New England Inflammation and Tissue Protection Institute at Northeastern University, exposed mice with lung tumors to respiratory hyperoxia at levels of 40-60 percent oxygen, comparable to what patients might receive in the hospital. Another group of mice breathed air, which is approximately 21 percent oxygen. Tumors in mice that received supplemental oxygen shrank — some regressed completely — and the animals were more likely to survive than those on room air.

The team hopes to see clinical trials of respiratory hyperoxia in combination with immunotherapies to see whether it can help cancer patients. They also noted that the effects might be stronger in combination with another agent that blocks the receptor where adenosine binds to inhibit the immune cells.

For Jackson, the discovery is personally rewarding. Fourteen years ago, his older brother, James F. Jackson, died at 57 of renal cell carcinoma. In 1986, James had received the National Science Foundation Presidential Award for Excellence in Science Teaching.

“Jim was my childhood mentor and the reason I am a scientist today,” Edwin Jackson said. “His three years of treatment was an emotional and frustrating time for me because we didn’t have the right tools to help him. I started doing cancer research because of that experience, and I hope these results will one day prevent suffering and loss by countless other families.”

Other study investigators included researchers from the Dana-Farber Cancer Institute, Harvard Medical School and the University of Miami.

The project was funded by NIH, the National Cancer Institute and Northeastern University.

Medicare could save $150 million on Part D plans

Using an intelligent, rather than random, method for assigning people with schizophrenia to Medicare Part D prescription drug coverage plans could save Medicare and patients a combined $150 million annually, a Graduate School of Public Health analysis discovered.

The results are reported in the journal Health Affairs and build upon an earlier study finding that Medicare could have saved more than $5 billion in its Part D low-income subsidy program in 2009 had it used intelligent assignment among all beneficiaries who received a subsidy.

Medicare Part D provides prescription drug coverage assistance to people enrolled in Medicare who have incomes below 150 percent of the federal poverty level. Since 2006, the government randomly has assigned low-income enrollees to standalone Part D plans, based upon the region in which they live.

Said lead author Yuting Zhang, health economics faculty member in the Department of Health Policy and Management: “If the government pilots intelligent assignment of Medicare Part D beneficiaries, people with schizophrenia would be an ideal group to start with. The majority of these patients are already randomly assigned to Part D plans. They spend considerably more on medication than the general Medicare population, but most of their drug spending is subsidized by the government, and these patients often have a difficult time selecting ideal plans themselves.”

Zhang and her team obtained data on nearly 120,000 beneficiaries with schizophrenia and developed a computer algorithm to intelligently assign them to plans available in their regions based on their medication needs.

Intelligent assignment translated into an annual savings of $466 per beneficiary with schizophrenia.

Schizophrenia — a chronic, disabling brain disorder often treated with medications — affects 2.6 percent of Medicare beneficiaries enrolled in standalone Part D plans.

More than 90 percent of people with the disorder are eligible for a low-income subsidy for their Part D prescription drug benefit, meaning they pay little or no premium for their Part D plan and have only nominal copayments.

Although Medicare beneficiaries are allowed to select a plan other than the one to which they were randomly assigned, there is little financial reason for people with schizophrenia to do so.

“This situation highlights why it would be beneficial for the government to use intelligent assignment,” said Zhang. “We recommend that Medicare use intelligent assignment as the default approach for all beneficiaries with schizophrenia who receive a low-income subsidy, and consider it as an option for all Part D beneficiaries, regardless of their income.”

Additional authors on this research were Seo Hyon Baik of public health and a colleague from Harvard.

This research was supported by National Institute of Mental Health and the Agency for Healthcare Research and Quality.

Grant fosters research careers

The University Honors College has received a three-year $150,000 grant from the Beckman Foundation to support the training of six undergraduate students with career interests in scientific research.

The first cohort of Beckman scholars will be supported from May 2015 through July 2016, including 10 summer weeks on both sides of the coming academic year.

Each scholar receives $18,200 in stipend and $2,800 in supply and travel money. Faculty mentors will receive $5,000 to undertake work associated with the scholar’s research experience: traveling to scientific meetings, purchasing scientific supplies and paying publication fees. During the second summer, the scholars also will attend the national Beckman research symposium where they will present their research work.

Edward M. Stricker — dean of the honors college, Bernice L. & Morton S. Lerner Chair and distinguished University professor of neuroscience — is the program director of the current award. Co-directors are Harvey Borovetz, a bioengineering faculty member in the Swanson school, and Jeff Brodsky, Avinoff chair of biological sciences in the Dietrich school. The 15 faculty mentors are:

• From the Dietrich school, in biological sciences: Tia-Lynn Ashman, Jeff Brodsky and Graham Hatfull; in neuroscience: Stephen Meriney, Linda Rinaman and Alan Sved; and in chemistry: Alexander Deiters, Sunil Saxena and Peter Wipf.

• From the Swanson school, in bioengineering: Lance A. Davidson, Steven R. Little and Sanjeev Shroff.

• With joint appointments: David A. Lewis (psychiatry and neuroscience), Michael A. Lotze (surgery and bioengineering) and William R. Wagner (surgery, bioengineering and chemical engineering).

Pitt has received this grant several times in the past, beginning in 1998.

—Compiled by Marty Levine


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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