Skip to Navigation
University of Pittsburgh
Print This Page Print this pages

January 5, 2017

Research Notes

Pittsburgh teen girls found to be only half as active as needed

A group of teenagers on the street.Teenage girls in Pittsburgh lag far behind the expected levels of physical activity for U.S. adolescent females, according to a new analysis based on a representative sample of that population. This study was led by researchers at Pitt’s School of Medicine and Graduate School of Public Health.

The findings, published in Medicine & Science in Sports & Exercise, the journal of the American College of Sports Medicine, suggest that teenage girls living in urban settings may need additional, targeted opportunities for physical activity to achieve the levels reached by their suburban and rural counterparts.

Said lead author Bonny Rockette-Wagner, director of physical activity assessment at public health: “Sadly, we found that only about 5 percent of the hundreds of girls who participated in our study met the minimum daily activity level recommended by national and international health agencies. Girls who were obese or had given birth in the last year were even less likely to achieve adequate levels of physical activity.”

The Pittsburgh Girls Study has been following girls in 89 Pittsburgh zip codes since 1999. Kathleen McTigue, faculty member in medicine and epidemiology and senior author of the study, spearheaded a National Institutes of Health (NIH)-funded ancillary study to examine step counts among the participants. The goal was to collect information on how many steps the girls took on a regular basis. Step counts were measured once a year from 2010 to 2013 using a pedometer. Activity data was reported on over 900 girls who were 14-17 years old when the pedometer study started.

Initially, on average, the girls took 5,614 steps per day with very little change in step counts over the four-year period. Typically, 10,000 steps per day is recommended as a daily minimum for girls this age. This level of activity should allow girls to meet the goal of 60 minutes per day of physical activity recommended for youth by the U.S. Centers for Disease Control and Prevention and the World Health Organization.

According to the National Health and Nutrition Examination Survey, which collects data across rural, suburban and urban settings, U.S. females ages 12-19 average 9,000 steps per day, compared to 11,000 steps for their male counterparts. The gap between males and females in teen years shows a widening from childhood, when at ages 6-11, girls average 12,000 steps per day and boys average 13,000.

“When we take into account that persistent and growing gap between boys and girls, and compare our findings in Pittsburgh to national averages, a concerning picture emerges: Urban teenage girls are significantly lagging behind in physical activity,” said Rockette-Wagner. “From previous studies, we know that this puts them at risk for poor quality of life, the development of chronic diseases and other negative health outcomes.”

In the Pittsburgh study, girls who identified as non-Hispanic African American averaged slightly more steps than their counterparts. Markers of poverty and poorer neighborhood environment also tended to be associated with slightly higher step counts in this population. Based on previous studies in urban populations, this counter-intuitive relationship between poverty status and activity could be due, in part, to the necessity of walking for transportation. However, it should be noted that, overall, activity levels were low for the majority of girls in the study, regardless of race, ethnicity or poverty.

The analysis also found that average steps per hour peaked near the start of the school day, 8-9 a.m., and again in the late afternoon, 4-5 p.m. And, more steps overall were accrued during school hours, 8 a.m.-3 p.m., than other periods of the day.

“This highlights the importance of school-based activity for these urban youths,” said Rockette-Wagner. “However, this finding shouldn’t underemphasize the importance of opportunities for safe physical activity outside of school. The dominance of school-based activity in our study also may suggest a lack of alternative options for these girls to get out and move when they are not in school.”

Future studies should focus on examining a large group of participants, similar to the Pittsburgh Girls Study, that also include youth living in other metropolitan settings so that comparisons can be made and further insights gained, Rockette-Wagner added.

Additional Pitt contributors on this study were Alison E. Hipwell and Andrea Kriska. A colleague from Indiana University of Pennsylvania also contributed.

Swanson faculty focus on clean energy research

In collaboration with the American Institute of Chemical Engineers (AIChE), the Swanson School of Engineering will be part of a new institute that will leverage a $70 million contribution by the U.S. Department of Energy (DOE) as part of its Manufacturing USA network.

The Rapid Advancement in Process Intensification Deployment (RAPID) Manufacturing Institute, led by AIChE, is the 10th and newest member of this network, which received a five-year commitment from DOE and from private partners and energy industries. The goal is to increase domestic productivity and efficiency of various forms of energy by 20 percent over the next five years through improved manufacturing processes.

The RAPID proposal selected Pitt to serve as one of eight lead institutions. The University will be responsible for strategic road mapping and oversight on all research activity in RAPID’s natural gas upgrading application focus area. Pitt will guide and coordinate member efforts from the portion of 75 industrial partners, 34 academic institutions, seven national laboratories, two other government laboratories and seven nongovernmental organizations in the RAPID community that are targeting natural gas research. The University will provide support through its labs and centers dedicated to energy, process intensification, advanced manufacturing and simulation modeling, and will leverage Swanson school faculty expertise in natural gas and unconventional fuels research.

Heading up the Pitt team will be the Swanson school’s Department of Chemical and Petroleum Engineering under the direction of Michael Matuszewski, faculty member and director of external relationships for the department, and Götz Veser, faculty member and associate director of the Center for Energy.

According to Veser, the Pitt team will serve as the first tier of communication with the RAPID leadership in evaluating and recommending selection of natural-gas-related projects. “Our focus is to identify more efficient and cost-effective methods to convert natural gas into clean energy and other useful products through advance manufacturing,” said Veser.

“Access to Marcellus and Utica shale deposits has created new opportunities to utilize our natural resources in pursuit of greater independence, and the University of Pittsburgh is geographically located and technically positioned perfectly to lead the efforts towards clean and efficient utilization of these resources.”

In addition, the Pitt team’s current industry partnerships help to provide a stronger connection to identifying potential end uses, complement existing energy and manufacturing technologies, and even build a more knowledgeable workforce.

Said Matuszewski: “The Swanson school’s partnership with industries such as Lubrizol Corporation — which is broad-based but includes a priority on process intensification research — reflects the mission of RAPID and the other manufacturing institutes to assure cooperation and to share approaches toward commercialization. Most importantly for Pitt, the RAPID framework will allow us to scale our existing collaboration model, almost instantaneously; we’ll be able to leverage the advances that RAPID supports to better train students with expertise in new technology approaches and the ability to engineer cutting-edge processes. Moreover, we will position all RAPID students to advance the U.S. workforce by invigorating it with advanced, environmentally conscious expertise and increasing high-tech job opportunities to further strengthen our country’s manufacturing industry.”

Full antibiotics better for young kids’ ear infections

baby girl holding her ear in painIn a trial conducted at Children’s Hospital and the School of Medicine, researchers have demonstrated that when treating children ages 9-23 months with antibiotics for ear infections, a shortened course produces worse clinical outcomes without reducing the risk of antibiotic resistance or adverse events.

The results of the trial were published in The New England Journal of Medicine and highlighted by an accompanying commentary.

Acute otitis media is a bacterial infection of the middle ear behind the eardrum that causes it to become painfully inflamed. Three out of four children experience this infection within their first year. Consequently, it is the most common reason why children are prescribed an antibiotic.

Said Alejandro Hoberman, chief of the Division of General Academic Pediatrics at Children’s and the Jack L. Paradise Endowed Professor of Pediatric Research in the School of Medicine: “Given significant concerns regarding overuse of antibiotics and increased antibiotic resistance, we conducted this trial to see if reducing the duration of antibiotic treatment would be equally effective along with decreased antibiotic resistance and fewer adverse reactions.”

In the current trial, 520 children with acute otitis media randomly were assigned to either a standard 10-day regimen of the antibiotic amoxicillin-clavulanate or a shortened five-day treatment followed by five days of placebo. Neither the study participants nor the physicians knew which group the participant was assigned to.

Children were followed starting in October through the rest of the annual respiratory-infection season, and had a final visit during the following September.

Researchers found that the risk of treatment failure in the five-day group (34 percent) was more than twice the risk in the 10-day group (16 percent). The results were significant when considering the trial design, which was set up to find out whether the five-day treatment would be as good as the 10-day regimen, Hoberman said. Instead, the results clearly showed that not only was the initial assumption proven wrong, but the 10-day treatment was far more effective.

When they tested the presence of antibiotic-resistant bacteria through nasopharyngeal (back of the nose) swabs, there was no decrease in the five-day group as might have been expected with a shorter duration of antibiotics. Also, reduced-duration antibiotics did not decrease the risk of frequent adverse events like diarrhea or diaper rash.

When testing for the risk of a recurrent infection, researchers found that it was higher when children were exposed to three or more children for 10 or more hours per week, such as in a day care setting, or if the initial infection occurred in both ears as opposed to just one ear.

Importantly, the study also showed for the first time that almost half the children in whom residual fluid was observed in the middle ear after treatment had a recurring infection, a significantly higher percentage when compared to children without any residual fluid in the middle ear.

The marked superiority of the 10-day regimen over the five-day regimen led the independent safety monitoring board overseeing the trial to conclude it prematurely as the primary end point was achieved.

“The results of this study clearly show that, for treating ear infections in children between 9 and 23 months of age, a five-day course of antibiotic offers no benefit in terms of adverse events or antibiotic resistance,” said Hoberman. “Though we should be rightly concerned about the emergence of resistance overall for this condition, the benefits of the 10-day regimen greatly outweigh the risks.”

The study was supported by a contract from the National Institute of Allergy and Infectious Diseases and by Clinical and Translational Science Awards from the National Center for Research Resources, now at the National Center for Advancing Translational Sciences, NIH.

Other Pitt authors of the study were Jack L. Paradise, Howard E. Rockette, Diana H. Kearney, Sonika Bhatnagar, Timothy R. Shope, Judith M. Martin, Marcia Kurs-Lasky, Susan J. Copelli, D. Kathleen Colborn, Stan L. Block, John J. Labella, Thomas G. Lynch, Norman L. Cohen, MaryAnn Haralam, Marcia A. Pope, Jennifer P. Nagg, Michael D. Green and Nader Shaikh.

Online at multiple sites worse for kids than time spent

worried teenager using mobile phone and computer as internet cyber bullying stalked victim abusedCompared with the total time spent on social media, use of multiple platforms is more strongly associated with depression and anxiety among young adults, the Center for Research on Media, Technology and Health (CRMTH) found in a national survey.

The analysis, published in Computers in Human Behavior, showed that people who report using seven-11 social media platforms had more than three times the risk of depression and anxiety than their peers who use zero-two platforms, even after adjusting for the total time spent on social media overall.

Said lead author Brian A. Primack, director of CRMTH and assistant vice chancellor for health and society in the Schools of the Health Sciences: “This association is strong enough that clinicians could consider asking their patients with depression and anxiety about multiple platform use and counseling them that this use may be related to their symptoms. While we can’t tell from this study whether depressed and anxious people seek out multiple platforms or whether something about using multiple platforms can lead to depression and anxiety, in either case the results are potentially valuable.”

In 2014, Primack and his colleagues sampled 1,787 U.S. adults ages 19-32, using an established depression assessment tool and questionnaires to determine social media use.

The questionnaires asked about the 11 most popular social media platforms at the time: Facebook, YouTube, Twitter, Google Plus, Instagram, Snapchat, Reddit, Tumblr, Pinterest, Vine and LinkedIn.

Participants who used seven-11 platforms had 3.1 times the odds of reporting higher levels of depressive symptoms than their counterparts who used zero-two platforms. Those who used the most platforms had 3.3 times the odds of high levels of anxiety symptoms than their peers who used the least number of platforms. The researchers controlled for other factors that may contribute to depression and anxiety, including race, gender, relationship status, household income, education and total time spent on social media.

Primack, who also is a medicine faculty member, emphasized that the directionality of the association is unclear.

“It may be that people who suffer from symptoms of depression or anxiety, or both, tend to subsequently use a broader range of social media outlets,” he said. “For example, they may be searching out multiple avenues for a setting that feels comfortable and accepting. However, it could also be that trying to maintain a presence on multiple platforms may actually lead to depression and anxiety. More research will be needed to tease that apart.”

Primack and his team propose several hypotheses as to why multi-platform social media use may drive depression and anxiety:

• Multitasking, as would happen when switching between platforms, is known to be related to poor cognitive and mental health outcomes.

• The distinct set of unwritten rules, cultural assumptions and idiosyncrasies of each platform are increasingly difficult to navigate when the number of platforms used rises, which could lead to negative mood and emotions.

• There is more opportunity to commit a social media faux pas when using multiple platforms, which can lead to repeated embarrassments.

Said co-author César G. Escobar-Viera, a postdoctoral research associate at the Health Policy Institute and at CRMTH: “Understanding the way people are using multiple social media platforms and their experiences within those platforms — as well as the specific type of depression and anxiety that social media users experience — are critical next steps. Ultimately, we want this research to help in designing and implementing educational public health interventions that are as personalized as possible.”

A. Everette James, director of the Health Policy Institute, was senior author of the research publication. Additional Pitt authors were Ariel Shensa, Erica Barrett, Jaime E. Sidani and Jason Colditz.

The research was supported by NIH.

Cancer gene affects growth of pediatric liver tumors

Researchers at the School of Medicine and Children’s Hospital have uncovered how a key cancer gene works to accelerate cell growth in a mouse model of pediatric liver tumors. The results provide a better understanding of how inhibition of this gene can be used to combat the disease, and also suggest that doing so may be associated with fewer side effects than originally assumed.

The findings were published in the Journal of Biological Chemistry, and selected as one of the journal’s “Papers of the Week.”

The new research focuses on one of cancer’s key genetic players, a gene called Myc.
Said lead study investigator Edward Prochownik, director of oncology research at Children’s Hospital and the Paul C. Gaffney Professor of Microbiology and Molecular Genetics in the School of Medicine: “Understanding how Myc leads to tumor growth can provide valuable insight we can use to treat the disease, since at least 50 percent of all cancers overexpress Myc in some way.”

Prochownik’s research concentrates on the role of Myc in liver tumors. His team previously showed that although Myc plays a variety of roles in healthy dividing cells, it is not important for normal liver cell growth and regeneration. In fact, the Myc gene can be deleted from normal liver cells without affecting their long-term regenerative potential, as Prochownik and his colleagues reported in other work earlier this year.

In their current work, researchers studied the gene’s role in a mouse model of hepatoblastoma, a form of liver cancer that occurs in children, typically under the age of 3. Using genetic engineering techniques, the team induced hepatoblastoma tumors in mice that either did or did not have Myc in their liver cells. They found that mice lacking Myc in their liver cells generated tumors more slowly and survived longer than expected.

“Mice lacking liver Myc still developed tumors, but the tumors grew more slowly, suggesting that tumor growth, but not initiation, is dependent on Myc,” explained Prochownik.

Subsequent experiments showed that Myc promotes tumor growth by turning up the cell’s thermostat, raising its rate of metabolism so it can supply all of the metabolic building blocks and energy needed for rapid tumor growth. Prochownik and his colleagues believe that the different needs for Myc in normal versus tumor growth may be due to the fact that, in the latter case, this “metabolic thermostat” is turned up higher and therefore is more Myc-dependent. The more controlled conditions that exist with normal liver regeneration are therefore much less Myc-dependent.

Given that Myc plays such an important role in many cancers, a drug that inhibits it is an attractive therapeutic, explained Prochownik. However, because Myc is expressed in normal cells as well as cancerous ones, there have been concerns in the field that inhibiting the gene would produce too many detrimental side effects.

“Our research strongly suggests that this is not the case. Normal cells are not dependent on Myc the way that tumor cells are, so a Myc inhibitor could selectively target cancer cells while sparing healthy cells,” he added.

Over the past several years the team has developed several Myc inhibitors and they now are working to improve the drugs’ efficacy in cell culture and animal models of cancer. So far, they are proving to be effective in models of multiple myeloma and neuroblastoma, Prochownik said.

“Although they are not quite ready to give to patients yet, these compounds are a very exciting approach to treating a variety of cancers,” he added.

This research was supported by NIH.

Additional Pitt co-authors of the paper included Huabo Wang, Jie Lu, Lia R. Edmunds, Sucheta Kulkarni, James Dolezal, Junyan Tao, Sarangarajan Ranganathan, Laura Jackson, Marc Fromherz, Donna Beer Stolz, Radha Uppala, Sivakama Bharathi, Satdarshan P. Monga and Eric S. Goetzman.

Molecular changes during exercise examined in study

Male cyclist in rugged terrainPhysical activity is good for our overall well-being. Yet science has never determined exactly why that is. Pitt has been chosen by NIH for a large-scale collaboration to investigate why being active is beneficial for our health.

School of Education faculty member John M. Jakicic will lead Pitt’s contributions to the molecular transducers of physical activity in humans program, which seeks to fully understand how physical activity affects the human body at the molecular level.
Ultimately, the findings of this endeavor could assist health professionals with physical-activity recommendations and strategies for individuals at various stages of life and with particular health needs.

The Pitt team is one of 19 research centers in the nation to be selected for this collaboration and will share approximately $170 million over the next six years for program research. This will be the largest-ever NIH investment into the study of how physical activity improves health and prevents disease.

The research teams will perform individual projects centered around the examination of internal bodily elements — hormones, nucleic acids, proteins, etc. — that transmit the health effects of physical activity. They then will work to determine how certain variables — age, sex and fitness level, among others — alter these molecular messengers. All of the findings will be housed in a publicly accessible database that future researchers can use to further the field of study.

The team led by Jakicic, chair of the Department of Health and Physical Activity in the School of Education, is one of six research teams that will recruit healthy adults from diverse racial and ethnic backgrounds for an intensive exercise study. They will collect blood, urine and tissue samples from active and sedentary volunteers performing resistance and aerobic exercises. These samples will be shared with the other research teams in the collaboration.

Other Pitt faculty members on the team are Daniel E. Forman, chair of the Section of Geriatric Cardiology in the Department of Medicine; Erin E. Kershaw, chief of the Division of Endocrinology and Metabolism in the Department of Medicine; Anne B. Newman, chair of the Department of Epidemiology in the Graduate School of Public Health; Bradley C. Nindl, director of the Neuromuscular Research Laboratory in the Department of Sports Medicine and Nutrition in the School of Health and Rehabilitation Sciences; Lindsay C. Page, faculty member in the School of Education and a research scientist at the Learning Research and Development Center; and Renee J. Rogers, faculty member in health and physical activity at the School of Education.

Lung inflammation in CF studied

The chronic lung inflammation that is a hallmark of cystic fibrosis has been linked to a new class of bacterial enzymes that hijack the patient’s immune response and prevent the body from calling off runaway inflammation, according to a laboratory investigation led by the School of Medicine.

The discovery, published in the Proceedings of the National Academy of Sciences, gives scientists two avenues to explore for the creation of therapies that could interrupt or correct this interference by the opportunistic bacterium Pseudomonas aeruginosa, which disproportionately infects people with cystic fibrosis.

Said Jennifer M. Bomberger, faculty member in the Department of Microbiology and Molecular Genetics and senior author on the study: “There are about 30,000 patients in the U.S. with cystic fibrosis, and hundreds of thousands more with other chronic lung diseases. Once these diseases progress to the point that the patient is chronically infected with P. aeruginosa, current antimicrobial therapies are no longer effective and there are very few treatment options left. Lung damage from these chronic P. aeruginosa infections, coupled with a robust but unproductive inflammatory response to the infection, will eventually lead to respiratory failure in the patient and the need for a lung transplant.”

Cystic fibrosis is caused by a genetic mutation that makes it difficult for patients to clear infections, allowing microorganisms to repeatedly infect the respiratory tract. By the time they reach adulthood, most cystic fibrosis patients are chronically infected with P. aeruginosa because this particular bacterium has an exceptional ability to outcompete other microorganisms and establish a stronghold in the lungs.

Aiding its ability to outfight other infections, P. aeruginosa thrives when the body creates an inflammatory response aimed at isolating foreign invaders and attracting white blood cells to fight them. The body’s own inflammatory response to fight infection is a major part of what actually damages a cystic fibrosis patient’s lungs to the point that they no longer function.

Bomberger’s team, in collaboration with a Dartmouth colleague, discovered that P. aeruginosa perpetuates inflammation by secreting an enzyme called Cif that sabotages the body’s ability to make a key molecule called a “pro-resolving lipid mediator” and put a stop to the inflammatory response it started.

The scientists confirmed this mechanism by analyzing secretions drawn from the lungs of cystic fibrosis patients seen at Children’s Hospital and linking their findings to patient records. Patients with higher Cif levels in their lung secretions had reduced biological signaling to stop inflammation and increased levels of IL-8, a marker for inflammation. Increased Cif levels also correlated with reduced lung function, which leads to disease progression in patients.

Previous studies in mice indicated that artificially boosting the levels of the pro-resolving lipid mediator reduces the inflammatory response and promotes clearance of P. aeruginosa in a pneumonia model. Bomberger, with colleagues from the University of California-Davis, is exploring an alternative strategy to inhibit Cif activity, stopping the problem before it begins.

“It will be key to devise a way to remove P. aeruginosa’s ability to capitalize on the body’s natural inflammatory response, without eliminating that response,” said Bomberger. “Inflammation is happening for a reason — to clear infection. We just need it to temper the response when it is not effectively doing its job or is no longer needed.”

Becca A. Flitter of Pitt was a lead author on this study; other Pitt authors were Taylor Eddens, Jay K. Kolls, Daniel H. Kwak, Xinyu Liu and Janet S. Lee. Researchers from Harvard also contributed.

This research was funded by NIH, a Gilead Sciences Research Scholars in Cystic Fibrosis Award, the Cystic Fibrosis Foundation and a Munck-Pfefferkorn Award.

NASA funds microstructure simulation for 3-D printing

Additive manufacturing (AM) researchers at the Swanson school and simulation software company ANSYS, Inc. are among 13 university-led proposals to capture an early stage innovations (ESI) grant from NASA’s space technology research grants program. ESI grants promote innovative, early-stage technologies that address high-priority needs of America’s space program.

The Pitt team’s three-year, $500,000 award, “Prediction of Microstructure Evolution in DMLM (Direct Material Laser Melting) Processed Inconel 718 With Part Scale Simulation,” was funded in the modeling and simulation-based certification of additive manufacturing processing parameters category. Principal investigator is Albert To, faculty member in mechanical engineering and materials science and director of the ANSYS Additive Manufacturing Research Laboratory. Co-PI is Wei Xiong, also a faculty member in mechanical engineering and materials science.

Said To: “Additive manufacturing now allows us to produce complex metal components that are strong enough to replace machined parts in mechanical applications. However, because of the process parameters and materials used in AM, the microstructure within a part or between different parts can vary widely. Our research will focus on developing a new simulation tool to predict the microstructure evolution and stability of Inconel 718, a common nickel superalloy used in laser-based AM in industry.”

The research team’s proposal noted that NASA is keenly interested in improving the performance of structural components for high-temperature applications such as jet engine parts, where both creep and strength are critical and need to be anticipated.

According to NASA, the goal of the space technology research grants program is to accelerate the development of space technologies in their earliest stages to enable future systems capabilities and missions for NASA, other government agencies and the commercial space sector.

The program is funded by NASA’s Space Technology Mission Directorate.

Targeted therapy needed for brain metastases in breast cancer

Researchers at the University of Pittsburgh Cancer Institute (UPCI) and Magee-Womens Research Institute (MWRI) have discovered molecular changes in the primary tumor of breast cancer patients who developed brain metastases. The finding is expected to lead to improved diagnosis and targeted therapies.

The results, to be published in the Journal of the American Medical Association (JAMA) Oncology and presented at the 2016 San Antonio Breast Cancer Symposium, indicate that patients’ treatments should be tailored not only for the original breast cancer, but also the brain tumors, according to Adrian Lee, director of the Institute for Precision Medicine, a joint effort by Pitt and UPMC, and director of the Women’s Cancer Research Center, a collaboration between UPCI and MWRI.

Said Lee: “The brain is a common and catastrophic site of metastasis for breast cancer patients. Our study showed that despite the large degree of similarity between the initial breast tumor and the brain metastatic tumor, there were enough alterations to support comprehensive profiling of metastases to potentially alter the course of treatment.”

There are many types of breast cancers, and about 20 percent of them are identified as HER2-positive, meaning the cancer cells have more of a protein called HER2 that causes the cells to grow faster than those with normal levels of the protein. These patients’ cancers typically respond to targeted therapies. However, breast cancer patients with brain metastases who are identified as HER2-negative do not respond favorably to the same therapies.

Lee’s research team set out to determine if there were molecular differences in the primary breast tumors and their patient-matched brain metastatic tumors that would enhance treatment options.

Little research is available because there are few opportunities to study primary breast tissue with their patient-matched brain metastases. The research team tested tumors from 20 patients from two academic institutions, Pitt and the Royal College of Surgeons in Ireland. Among the discoveries was that the primary tumor initially identified as HER2-negative actually switched to HER2-positive in the metastatic brain tumor.

“This now means we can screen for presence of HER2 so that we can change and target the therapy to improve outcomes for our patients,” said Lee.

Additional UPCI authors on this study were Nolan Priedigkeit, Yijing Chen, Ahmed Basudan, Rebecca J. Watters, Roby Thomas, Peter C. Lucas, Rohit Bhargava, Ronald L. Hamilton, Shannon L. Puhalla, Nancy E. Davidson, Steffi Oesterreich and Adam M. Brufsky.

Colleagues from the Foundation Medicine, in Cambridge, Mass., the Royal College of Surgeons in Ireland and the University of Iowa also contributed.

This research was supported by the Breast Cancer Research Foundation, National Cancer Institute, Fashion Footwear Association of New York, the Shear Family Foundation, Magee-Womens Research Institute and Foundation, Susan G. Komen for the Cure, National Institute of General Medical Sciences and the Irish Cancer Society Collaborative Cancer Research Centre.

Antidote for
carbon monoxide poisoning developed

Researchers from the School of Medicine and UPMC have engineered a protein that reverses carbon monoxide (CO) poisoning in mice, a discovery that could lead to the creation of the first antidote in humans to the often deadly poisoning, according to research published in Science Translational Medicine.

CO poisoning is responsible for more than 50,000 emergency room visits in the United States annually, and is one of the leading global causes of poisoning death. A colorless, odorless gas, CO is extremely effective at replacing oxygen molecules in hemoglobin, the oxygen-carrying protein in blood. CO exposure also results in debilitating effects on the body and the brain, including cognitive deficits that in some cases can persist months or years after a poisoning event.

Said Mark T. Gladwin, chair of medicine in the School of Medicine, Dr. Jack D. Myers Professor of Internal Medicine and director of the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute: “Despite being the most common poisoning worldwide, we still do not have an effective antidote for CO exposure. Our protein is extraordinarily effective at scavenging CO from the blood, and could potentially prove to be a significant advance in the treatment of CO poisoning.”

Current treatment options for CO poisoning — administering 100 percent oxygen or using a pressurized hyperbaric chamber to administer oxygen at greater than normal air pressure — focus on trying to replace CO in blood with oxygen as quickly as possible. However, both these treatments are only moderately effective. Moreover, transporting patients to a hyperbaric chamber requires a significant amount of time, and many poisoned patients may not be stable enough for this therapy.

When studying neuroglobin (Ngb), a hemoglobin-like protein present in the brain, Gladwin and his team discovered it could bind CO with an unusually high affinity. Based on knowledge of how the protein works, researchers engineered a mutant version of the protein, called Ngb H64Q, that was an even better scavenger of CO.

In a purified sample of red blood cells infused with CO, they found that Ngb H64Q was 1,200 times faster at forcing CO to release itself from being bound to hemoglobin than just air alone. When tested in a mouse model of non-lethal CO poisoning, Ngb H64Q was significantly better at removing CO from hemoglobin than 100-percent oxygen treatment. The normal half-life of CO in humans after poisoning (time it takes for half of the CO to be eliminated from the body) is 320 minutes, and even with 100-percent oxygen therapy, that time is 74 minutes. With the antidote therapy, the CO half-life was reduced to only 23 seconds.

In a mouse model with lethal levels of CO poisoning, seven out of eight mice treated with Ngb H64Q (87.5 percent) survived the duration of the experiment, while 10 percent or less survived in the control groups. Additionally, the antidote restored blood pressure and improved the amount of oxygen that was present in tissues, suggesting that Ngb H64Q works by scavenging CO from hemoglobin and allowing oxygen to bind in its place, thus restoring normal oxygen delivery.

Importantly, CO bound to Ngb H64Q was detected in the urine of mice shortly after treatment, which indicated that the rodents were able to excrete the antidote from the body without any major toxic effects.

“If approved, this antidote could be rapidly administered to victims in the field, eliminating costly delays that occur with current treatment options,” Gladwin said. “We still need extensive safety and efficacy testing before an antidote is available on the shelf, but our early results are very promising.”

Researchers plan to scale up their safety and efficacy testing in animal models and hope to advance to clinical trials within the next few years.

Pitt’s Ivan Azarov, Ling Wang and Jason J. Rose were the study’s lead authors. Additional Pitt contributors were Qinzi Xu, Xueyin N. Huang, Ying Wang, Lanping Guo, Charles F. McTiernan, Christopher P. O’Donnell, Sruti Shiva and Jesús Tejero. Colleagues from Wake Forest University also contributed.

The study was supported in part by the National Heart, Lung and Blood Institute SMARTT (Science Moving towArd Research Translation and Therapy) program, the Institute for Transfusion Medicine, the Hemophilia Center of Western Pennsylvania and NIH.

New way to capture, convert atmospheric carbon dioxide

Research at the Swanson school focused on developing a new catalyst that would lead to large-scale implementation of capture and conversion of carbon dioxide (CO2) was published in the Royal Society of Chemistry journal Catalysis Science & Technology.

Principal investigator was Karl Johnson, the William Kepler Whiteford Professor in the school’s Department of Chemical and Petroleum Engineering. Postdoctoral associate Jingyun Ye was lead author. The article builds on Johnson’s previous research that identified the two main factors for determining the optimal catalyst for turning atmospheric CO2 into liquid fuel. The research was conducted using computational resources at the Center for Simulation and Modeling.

Said Johnson: “Capture and conversion of CO2 to methanol has the potential to solve two problems at once: reducing net carbon dioxide emissions while generating cleaner fuels. Currently, however, it is a complex and expensive process that is not economically feasible. Because of this, we wanted to simplify the catalytic process as much as possible to create a sustainable and cost-effective method for converting CO2 to fuel — essentially to reduce the number of steps involved from several to one.”

Johnson and Ye focused on computationally designing a catalyst capable of producing methanol from CO2 and H2 using metal organic frameworks (MOFs), which potentially provide a pathway for a single-process unit for carbon capture and conversion. The MOFs could dramatically reduce the cost of carbon capture and conversion, bringing the potential of CO2 as a viable feedstock for fuels closer to reality.

“Methanol synthesis has been extensively studied because methanol can work in existing systems such as engines and fuel cells, and can be easily transported and stored,” he said. “Methanol is also a starting point for producing many other useful chemicals. This new MOF catalyst could provide the key to close the carbon loop and generate fuel from CO2, analogously to how a plant converts carbon dioxide to hydrocarbons.”

This work was supported by the U.S. Department of Energy.

Clean energy technologies possible via proton research

The motion of protons within water is an elusive area of science that is now of higher interest as a better understanding of how this motion occurs may lead to advancements in clean energy technologies.

Many processes, including vision, signaling in biological systems, photosynthesis and the operation of many fuel cells involve the motion of protons in water. Scientists are pursuing an enhanced understanding of that movement, which is needed to improve the technologies that depend on proton transfer.

An international team of scientists, including a Pitt faculty member and a Pitt graduate student, has obtained snapshots of the process by which a proton is relayed from one water molecule to the next. The research was published in Science.

Said co-author Kenneth Jordan, Richard King Mellon Professor and Distinguished Professor of Computational Chemistry in the Department of Chemistry in the Dietrich School of Arts and Sciences and co-director of the Center for Simulation and Modeling: “These measurements represent a major benchmark in our knowledge of how water conducts a positive electrical charge.”

Jordan’s research involved collaboration of experimental groups led by others at Yale and the University of Leipzig, and theory groups at the University of Washington. They collaborated for over a decade, focusing on the nature of excess protons in water.

The Grotthuss mechanism for proton conduction in water was introduced over two centuries ago. But the details supporting the theory have been murky due to the unpredictability of water molecules when they are near the excess proton.

A key tool in characterizing water networks is infrared spectroscopy, which determines the energies at which the atoms in molecules vibrate. These energies depend sensitively on the relative positions of the molecules.

Jordan said the rapid movement of water molecules makes it difficult to see and measure the movement of the protons when using infrared spectroscopy. That “blurring” limits the information that can be gathered using that tool.

The experimental team members solved this problem by obtaining the vibrational spectra of very cold clusters, which contain a small number of water molecules. They then switched from “regular” water to “heavy water,” which is water that contains a larger-than-normal amount of the hydrogen isotope deuterium.

Under these conditions, the vibrational signatures became dramatically sharper, making it possible to obtain a series of snapshots along the proton transfer pathway.
The other groups provided calculations that illuminated the physical mechanism that determined the pathway. The calculations revealed that the electric fields imposed on the excess proton by nearby molecules play a major role in establishing the proton transfer pathway.

Understanding of the factors influencing proton transfer gained in this study can be used in designing more efficient materials and devices for energy applications.
In addition to Pitt author Tuguldur Odbadrakh, researchers from Yale, the University of Chicago, Ohio State and Leipzig contributed.

Support for the research came from the U.S. Department of Energy, the National Science Foundation and the Collaborative Research Center of the German Research Foundation DFG.

—Compiled by Marty Levine

The University Times Research Notes column reports on funding awarded to Pitt researchers and on findings arising from University research. We welcome submissions from all areas of the University. Submit information via email to:, by fax to 412-624-4579 or by campus mail to 308 Bellefield Hall. For submission guidelines, visit

Leave a Reply