Esophagus stem cells discovered here

Despite previous indications to the contrary, the esophagus does have its own pool of stem cells, researchers from the School of Medicine reported in an animal study published online in Cell Reports. The findings could lead to new insights into the development and treatment of esophageal cancer and the precancerous condition known as Barrett’s esophagus.

According to the American Cancer Society, more than 18,000 people will be diagnosed with esophageal cancer in the U.S. this year and almost 15,500 people will die from it. In Barrett’s esophagus, the lining of the esophagus changes for unknown reasons to resemble that of the intestine, though gastro-esophageal reflux disease or GERD is a risk factor for its development.

Said senior investigator Eric Lagasse, pathology faculty member and director of the Cancer Stem Cell Center at the McGowan Institute for Regenerative Medicine: “The esophageal lining must renew regularly as cells slough off into the gastrointestinal tract. To do that, cells in the deeper layers of the esophagus divide about twice a week to produce daughter cells that become the specialized cells of the lining. Until now, we haven’t been able to determine whether all the cells in the deeper layers are the same or if there is a subpopulation of stem cells there.”

The research team grew pieces or “organoids” of esophageal tissue from mouse samples, and then conducted experiments to identify and track the different cells in the basal layer of the tissue. They found a small population of cells that divide more slowly, are more primitive, can generate specialized or differentiated cells and have the ability to self-renew, which is a defining trait of stem cells.

“It was thought that there were no stem cells in the esophagus because all the cells were dividing rather than resting or quiescent, which is more typical of stem cells,” Lagasse noted. “Our findings reveal that there indeed are esophageal stem cells, and rather than being quiescent, they divide slowly compared to the rest of the deeper layer cells.”

In future work, the researchers will examine human esophageal tissues for evidence of stem cell dysfunction in Barrett’s esophagus disease.

“Some scientists have speculated that abnormalities of esophageal stem cells could be the origin of the tissue changes that occur in Barrett’s disease,” Lagasse said. “Our current and future studies could make it possible to test this long-standing hypothesis.”

Co-investigators were pathology faculty Aaron DeWard and Julie Cramer.

The research was funded by the Commonwealth of Pennsylvania, the National Institutes of Health (NIH), the McGowan Institute and the pathology department’s postdoctoral research training program.

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Grant creates biodegradable implants, also school programs

Researchers have received another $1.5 million from the National Science Foundation (NSF) to continue a combined multi-university, private-industry effort to develop implantable medical devices made from biodegradable metals.

Body-degradable metals — usually magnesium-based — are not new, having been considered originally in the late 19th century. But, said William Wagner, director of the McGowan Institute for Regenerative Medicine and faculty member in surgery and in the Swanson School of Engineering’s bioengineering and chemical engineering departments: “The question comes when you start to design medical devices for a specific application and a clinical partner says, ‘We want that to be gone in a month, or a month-and-a-half, or we want that to be there for a year.’” Then you have to figure out how to meet those specifications, he said.

The Pitt team as well as collaborators at the University of Cincinnati and North Carolina Agricultural and Technical State University are creating new alloys and manufacturing processes that suit clinical demands.

The consortium seeks to design devices that can adapt to changes in a patient’s body and dissolve once healing has occurred, reducing the follow-up procedures and potential complications of major orthopaedic, craniofacial and cardiovascular procedures and sparing patients added pain and medical expenses.

Thus far, the consortium has created novel screws and plates for facial reconstruction, a stent to be used in kidney dialysis, a nerve guide and a ring that will assist in pulling together and healing ruptured ligaments. The group also has created a tracheal stent for pediatric patients whose tracheas are underdeveloped at birth and prone to collapse. Once the stent is implanted, Wagner, deputy director of the project and a principal investigator, said it would dissolve, obviating the need for a second procedure on the young patient.

The consortium’s original grant, received in 2008, was for a total of $18.5 million over five years, shared by the three institutions. The total of the grant extension is $4 million, including the $1.5 million received by Pitt.

Wagner said the project can be funded for up to 10 years, with the hope that the group effort will become self-sustaining. “Several devices are fairly far along in pre-clinical testing and are on the third, fourth or fifth prototype,” he said.

The universities also have involved several private enterprises in the project, including InCube Labs, nanoMag-Thixomat, ACell, OrthoKinetic Technologies, Fort Wayne Metals, General Nano and IonBond.

Grant funding also has allowed Pitt, with the assistance of faculty members in Pitt’s Department of Bioengineering and the McGowan institute, to help the North Carolina school to establish the first degree-granting program in bioengineering at any historically black college or university. The program currently offers bachelor’s and master’s degrees and ultimately aims to offer a PhD.

“There has been a lot of student exchange between the universities,” Wagner says. “It has been a good exercise for the trainees involved, as it spans the individual universities and reaches into active collaborations.”

In addition to undergraduate and graduate degrees, the research team, via the grant, has advanced STEM education to K-12 students in the Greensboro, N.C., Cincinnati, Ohio, and western Pennsylvania regions by converting its work into a curriculum for aspiring engineers, with particular attention given to underrepresented groups.

K-12 teachers also are invited to spend summer rotations in faculty-member laboratories to further broaden the transfer of scientific knowledge from the research effort.

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Dental medicine to study cancer’s spread to bones

With a $2 million, five-year grant from the National Cancer Institute (NCI), part of NIH, researchers at the School of Dental Medicine will examine the molecular mechanisms that allow certain cancers, particularly multiple myeloma, to spread to the bone. The project could lead to new interventions to prevent such metastases and perhaps slow down primary tumor growth.

As Hongjiao Ouyang, the project’s principal investigator, faculty member in restorative dentistry/comprehensive care and oral biology and a member of the Center for Craniofacial Regeneration, noted, about 30 percent of multiple myeloma patients are diagnosed after going to the dentist with jaw pain or suspicious lesions in the oral cavity. Multiple myeloma is a cancer of plasma cells that begins in the bone marrow and is known for eating away the bone. Even with treatment, the bone lesions rarely heal.

“This bone destruction is a significant cause of pain and mortality in this disease,” said Ouyang, an endodontist and bone biologist. “A better understanding of the molecular pathways that underlie this process could lead us to novel targets for treatment.”

Bone marrow stromal cells (BMSCs) reside in the bone marrow and with appropriate stimulation can give rise to bone-forming cells called osteoblasts, fat cells and other cells. In multiple myeloma, BMSCs produce growth factors and inflammatory proteins that boost tumor cells and activate osteoclasts, which are cells that break down bone while osteoblasts rebuild it as part of normal metabolism. In cancer, osteoclast activation makes holes in the bone that do not heal.

Ouyang’s team has found that the BMSCs in multiple myeloma patients, unlike those in healthy people, produce much more X-box binding protein (XBP1s), a molecule that has been shown in other tissues to regulate the production of inflammatory proteins. Their lab experiments showed that inducing healthy cells to produce XBP1s leads to changes in the bone microenvironment that support growth of multiple myeloma cells and osteoclast formation. Conversely, knocking out XBP1 production in multiple myeloma patient BMSCs corrected the abnormalities.

For the newly funded project, the team will determine the molecular mechanisms of the stromal XBP1 signaling in altering the bone microenvironment to favor multiple myeloma growth and bone destruction, as well as employ pharmacologic and genetic strategies to repress this molecule as a proof-of-concept for approaches to treat multiple myeloma bone disease.

“This could be helpful not only in treatment of multiple myeloma, but also in other cancers that spread to bone, such as breast, prostate and lung cancer, since BMSCs play a similar role in supporting tumor cell growth in these neoplastic diseases as well,” Ouyang said.

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$11 million grant from NIH establishes big data center

NIH has awarded Pitt an $11 million, four-year grant to lead a Big Data to Knowledge Center of Excellence, an initiative that will help scientists capitalize more fully on large amounts of available data and to make data science a more prominent component of biomedical research.

Noted Gregory Cooper, vice chair of the Department of Biomedical Informatics in medicine and director of the new Center for Causal Modeling and Discovery: Much of science focuses on understanding the “why” or “how” in nature, and now the challenge is to find these answers within terabytes and petabytes of data, or what is now known as big data.

“Individual biomedical researchers now have the technology to generate an enormous quantity and diversity of data,” said Cooper. “Adequately analyzing these data to discover new biomedical knowledge remains a major challenge, however. Our goal is to make it much easier for researchers to analyze big data to discover causal relationships in biomedicine.”

The Pitt Center for Causal Modeling and Discovery will be part of a national team addressing the challenges of big data in biomedicine.

According to center co-director Jeremy Berg, associate senior vice chancellor for science strategy and planning in the Health Sciences and director of the Institute for Personalized Medicine, researchers now have access to a tremendous amount of information from electronic health records, digital images and molecular analyses of genes, proteins and metabolites.

“The good news is that we have so much data. But the bad news is that we have so much data,” Berg said. “Our challenge is to find strategies that enable us to sort through all this collected information efficiently and effectively to find meaningful relationships that lead us to new insights in health and disease.”

A collaboration of researchers at Pitt, Carnegie Mellon, the Pittsburgh Supercomputing Center and Yale, the new center will develop and disseminate tools that can find causal links in very large and complex biomedical data.

The center includes a team that will develop and implement causal modeling and discovery algorithms, or processes, to support the data analyses of three separate investigative groups, each focusing on a distinct biomedical problem whose answer lies in a sea of data: cell signals that drive the development of cancer; the molecular basis of lung disease susceptibility and severity, and the functional connections within the human brain (the “connectome”).

Each project will act as a test bed for the development, rigorous testing and refinement of analytic tools. When successful, these algorithms and software likely can be applied to other biomedical research questions. The center will provide free, open-source software that scientists all over the world can use with their own datasets to uncover causal biomedical relationships. Their feedback will further enhance the algorithms and software.

Said center co-director Ivet Bahar, Distinguished Professor and JK Vries Chair, Department of Computational and Systems Biology in medicine: “The center also will be a training ground for the next generation of data scientists who will advance and accelerate the development and broader use of big-data science models and methods. We will create new educational materials as well as workshops and online tutorials to facilitate the use of causal modeling and discovery algorithms by the broader scientific community and to enable efficient translation of knowledge between basic biological and applied biomedical sciences.”

Other collaborators include the California Institute of Technology, Rutgers, the University of Crete and the University of North Carolina.

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GI scope sterilization proves better than disinfection; program for hand hygiene boosts compliance

National guidelines for the cleaning of certain gastrointestinal (GI) scopes are likely to be updated due to findings from a Pitt/UPMC infection-prevention team. The research and updated disinfection technique was presented at ID Week 2014, an annual meeting of health professionals in infectious disease fields, by senior author Carlene Muto, medicine faculty member and UPMC Health System director of infection prevention at UPMC Presbyterian Hospital.

Said Muto: “We are confident that the change from disinfection to sterilization of GI scopes is necessary in preventing serious infections.”

After tracking and monitoring an uptick in antibiotic-resistant infections in 2012 in patients who had undergone an endoscopic retrograde cholangiopancreatography (ERCP) procedure with flexible endoscopy scopes, UPMC began investigating the devices, which are equipped with an “elevator channel” used to deflect accessories passed through the biopsy channel and assist clinicians in examining a patient’s gastrointestinal tract. The elevator channel is most commonly found on ERCP and endoscopic ultrasound scopes.

UPMC took the scopes out of service, notified the manufacturer and began an investigation into the disinfecting process that takes place between each use. When it was ultimately determined that the normal process failed to eliminate all bacteria, UPMC switched to gas sterilization using ethylene oxide to ensure proper disinfection of the scopes.

“Throughout UPMC, no additional health care-associated infections have been linked to scopes since switching to sterilization,” said Muto.

Approximately 11 million gastrointestinal endoscopies are performed annually in the U.S. and contaminated scopes have been linked to more hospital-acquired infections than any other type of medical device.

Muto also presented findings about an initiative called Just Culture begun in June 2012 at UPMC Presbyterian. There, infection-prevention teams have improved hand washing and sanitizing compliance to nearly 100 percent among clinical staff through accountability and educational measures. In a separate effort at UPMC Mercy, rates of a deadly infection were reduced by educating patients about hand hygiene.

“Hand hygiene compliance in health care facilities nationwide is not satisfactory, yet is the single most important way to prevent infections,” said Muto. According to the U.S. Centers for Disease Control and Prevention, U.S. hospital patients contract an estimated 722,000 infections each year.

Through this coordinated program that includes education, videos, internal newsletter articles, posters and verbal reminders, health care personnel are held accountable for conscious disregard of patient safety, including hand hygiene. They are not held accountable for system failures. Staff who fail to wash or sanitize their hands are warned and may progress through disciplinary action for continual disregard for hand hygiene.

Within four months of launching the Just Culture initiative, hand hygiene compliance rates at UPMC Presbyterian increased from 70 percent to 99 percent. Since then, the near-perfect rates have been maintained with re-education and the cultural shift to accountability.

Said lead author Ashley Querry, infection prevention coordinator at UPMC Presbyterian: “Hand hygiene can be increased with educational campaigns, but we’ve found that these gains can only be sustained when a health system makes it unacceptable to be lax on hand-washing.”

At UPMC Mercy, infection prevention officials led another study to determine the effectiveness of efforts to encourage hand hygiene among patients.

Pre-packaged alcohol wipes were made available at patients’ bedsides and health care staff reminded, assisted and encouraged patients to use the wipes.

Rates of C. difficile, an antibiotic-resistant bacteria that causes inflammation of the colon and can be deadly, fell significantly after the patient encouragement program was implemented.

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NSF funds project upgrading computer infrastructure for research

Pitt has been awarded nearly $500,000 from NSF for a project to upgrade the University’s computer infrastructure for research initiatives.

The venture will enhance Pitt’s connection to major national research and education networks, providing additional bandwidth and capacity to computational resources, science centers and advanced networking. The project also will improve the campus connection to the University data center that hosts high-performance computing resources, which are used by researchers for sophisticated simulation, modeling and data analysis.

Computing Services and Systems Development will work with teams within the University and other NSF-funded organizations to design and implement a Science DMZ, which is a subnetwork designed by the Department of Energy for data-intensive science. This will improve the secure movement of scientific data among researchers collaborating on local, national and international projects.

Said Jinx Walton, chief information officer: “The development of a Science DMZ will facilitate the high-speed transfer of large data sets by those Pitt scientists and researchers taking advantage of high-performance computing.”

Research projects that will benefit from the upgrade include the Pittsburgh Genome Resource Repository, the massively parallel simulations of turbulent flows conducted by the Laboratory for Computational Transport Phenomena and the Department of Physics and Astronomy’s Tier-3 simulations and data analysis in preparation for the anticipated Large Hadron Collider run in 2015.

In addition to stronger networking connections to Pitt’s University Data Center, the project will upgrade Pitt’s connection to the Three Rivers Optical Exchange from 10 Gbps (gigabits per second) to 100 Gbps and will provide additional bandwidth and capacity to the Pittsburgh Supercomputing Center and to research and education networks, including Internet2, the Energy Sciences Network (ESnet) and the Extreme Science and Engineering Discovery Environment (XSEDE).

Internet2, which operates the nation’s fastest research and education network, is a member-owned advanced technology community founded by the nation’s leading higher education organizations. Internet2 serves as the backbone infrastructure to ESnet and XSEDE.

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DOD award funds research into whole-eye transplantation

Medicine researchers have been awarded $1.25 million from the Department of Defense (DOD) to fund two projects that aim to establish the groundwork for the nation’s first whole-eye transplantation program.

Offered through the DOD’s vision research program, the grants support conceptually innovative research that ultimately could lead to critical discoveries or major advancements. The Pitt researchers will lead a multidisciplinary consortium that includes clinicians and scientists from Harvard and the University of California-San Diego.

Although corneal transplants are performed routinely today, whole-eye transplantation has remained an unrealized goal in vision restoration because of challenges related to immune rejection and re-establishing the connectivity of the optic nerve to the visual centers in the brain.

The Audacious Restorative Goals in Ocular Sciences (ARGOS) Consortium established at Pitt will be the first cross-disciplinary, systematic attempt to explore strategies to enable corneal regeneration, retinal cell survival, long-distance optic nerve regeneration with cortical integration and whole-eyeball transplantation.

Said principal investigator Vijay Gorantla, faculty member in the Department of Plastic Surgery and the administrative medical director of the Pittsburgh reconstructive transplant program at UPMC: “Recent advances in our understanding of retinal ganglion cell survival and successes with optic nerve regeneration in experimental studies strengthen our hope that whole-eye transplantation is an audacious yet achievable goal. Our experience with transplanting complex immunogenic tissues, such as the hand, will help us optimize treatments for rejection in eye transplants.”

According to the DOD, blast injuries are the most common for soldiers wounded in action, with up to 40 percent of blast injuries affecting the eyes. Approaches to minimize worsening of injury to the eye after trauma, preserve and protect residual retinal and optic nerve function and restore vision are all goals that will be investigated.

Said co-principal investigator Joel Schuman, chair of the Department of Ophthalmology and director of the UPMC Eye Center: “This is an aggressive program with very high-risk and high-reward scenarios. We’re excited to be leading the project and honored to be collaborating with global leaders in optic nerve regeneration. By solving one facet of the problem at a time, the long dreamed-of goal of whole-eye transplantation may be possible with the promise of a better life for millions of patients worldwide.”

In a related project led by principal investigator Kia Washington, a plastic surgery faculty member, the research team will focus on establishing baseline viability and structural integrity in an animal model of whole-eye transplantation. The researchers will examine immune rejection and evaluate the usage of extracellular matrix therapy for improvement of optic nerve function after whole-eye transplantation.

Said Washington: “We have successfully performed an eye transplant in a small animal model. This ongoing project may eventually lead to restoration of vision after trauma or degenerative disease.”

The Louis J. Fox Center for Vision Restoration will provide additional funding.

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Grant will refine quantitative biology pedagogy nationally

Math is increasingly important to understanding and investigating the world of biology because quantitative biology, computational biology and computer-based modeling approaches have emerged as important modes of inquiry.

But, said Samuel Donovan, a biology lecturer in the Dietrich School of Arts and Sciences, teaching methods haven’t always kept pace with developments in the field. In order to help bridge the divide and make sure that undergraduate students nationwide are prepared to engage with modern biology, Donovan and colleagues at the University of Wisconsin-Madison and The College of William and Mary recently were awarded a $2.9 million grant from NSF to establish the Quantitative Undergraduate Biology Education and Synthesis (QUBES) project.

“Faculty development is key to improving undergraduate biology education,” said Donovan, principal investigator on the grant. “Biology is very dynamic right now, and faculty who earned their PhDs 10 years ago are likely to teach new techniques with which they don’t have direct experience. Adding to this challenge is the fact that there are diverse types of undergraduate institutions and an uneven distribution of expertise in quantitative biology. Not everyone has the luxury of having a dedicated quantitative biologist down the hall to consult with.”

Donovan’s team plans to leverage existing information and communication technologies as part of a cost-effective and scalable solution to the problem. Using a collaborative platform developed at Purdue, QUBES will work with faculty groups to share pedagogic techniques and expertise on data management, data visualization and other aspects of quantitative biology nationwide.

“Biologists are working online. They often share their data and make analysis tools publicly accessible. Undergraduates need to learn these research tools,” Donovan said. The way research is done today, you can access a supercomputer from your laptop, and we need to help teachers take advantage of these resources and use them with students.”

At the end of the grant, Donovan hopes that the project will have helped to change the culture of undergraduate biology education so that what goes on in classrooms more closely reflects the work that scientists do.

—Compiled by Marty Levine

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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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