November 2010 | VOL. 9, NO. 11 | www.McGowan.pitt.edu
Origin of Sporadic Breast Cancer
Research efforts in the laboratory of McGowan Institute for Regenerative Medicine affiliated faculty member Jean Latimer, PhD, assistant professor at the University of Pittsburgh in the Department of Obstetrics, Gynecology and Women's Health and also a faculty member in the Cellular and Molecular Pathology Graduate Training Program and the University of Pittsburgh Cancer Institute, focus on DNA repair deficiencies as a causative factor in breast carcinogenesis. Dr. Latimer's laboratory has developed a multiple-lineage tissue engineering system for primary culture of Human Mammary Epithelial Cells. Dr. Latimer has also used this methodology to culture breast tumors as well as non-diseased tissue with a success rate of 85%. In these studies her laboratory measured DNA repair capacity as an etiological factor in breast tumorigenesis.
Dr. Latimer's most recent paper entitled "Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer" will appear in an upcoming edition of the Proceedings of the National Academy of Sciences of the USA.
In this paper, she writes that, "The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only about 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or they have not yet been identified. In striking contrast, we now show that 19/19 stage I breast tumors tested with the functional unscheduled DNA synthesis (UDS) assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (N = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis."
By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples vs. normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNAse protection. These results were confirmed at the protein level for 5 NER gene products.
Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.Read more…
Plans for the 10th Annual McGowan Institute for Regenerative Medicine Scientific Retreat is now open. The Retreat is set to take place on March 6-8, 2011 at Nemacolin Woodlands Resort. The poster session will also begin on the evening of March 6, 2011, at which time there will be an informal mixer. Under the leadership of Dr. William Wagner, the program committee is planning an exciting group of speakers and topics. The program will include:
- Distinguished Lecturer: Leonard Zon, MD-Harvard
- John DeFord- VP Science/Technology-CR Bard
- Bruno Gridelli, MD- Medical and scientific director, UPMC International & Commercial Services Division, and medical and scientific director of ISMETT
In addition, working sessions will include topics in the areas of Cell Therapy, Tissue Engineering and Medical Devices.
In addition to the outstanding scientific program, once again the Office of Enterprise Development (OED) is hosting the "Innovator Elevator Pitch." This event will consist of a series of scheduled brief presentations from participating faculty on the value of their technology to an audience which will include industry and venture capitalist participants. The external participants will provide commentary on the presented technology. This event will be a great opportunity to present the clinical value of your work to industry participants who may be interested in exploring collaboration or licensing opportunities.
The on-line registration will be open in December.
McGowan Institute for Regenerative Medicine faculty member Andrew Schwartz, PhD, professor of neurobiology at the University of Pittsburgh, is part of a multi-institute team of researchers working on a $34.5 million Defense Advanced Research Projects Agency (DARPA) contract awarded to the Johns Hopkins University Applied Physics Laboratory (APL) to manage the development and testing of the Modular Prosthetic Limb (pictured), or MPL, on a human subject, using a brain-controlled interface. APL scientists and engineers developed the underlying technology under DARPA's Revolutionizing Prosthetics 2009 program, an ambitious 4-year effort to create a prosthetic arm that would by far eclipse the World War II era hook-and-cable device used by most amputees. The program has already produced two complex prototypes, each advancing the art of upper-arm prosthetics.
The final design—the MPL—offers 22 degrees of motion, including independent movement of each finger, in a package that weighs about 9 pounds, the weight of a natural limb. Providing nearly as much dexterity as a natural limb, the MPL is capable of unprecedented mechanical agility, and is designed to respond to a user's thoughts. Along with Dr. Schwartz and his team of scientists at the University of Pittsburgh, APL will be working closely on the project with the California Institute of Technology, also for their experience in brain computer interfaces; the University of Chicago, for its expertise in sensory perception; the University of Utah, for its capabilities in developing implantable devices suitable for interfacing with the human brain; and HDT Engineered Technologies, for its skill in building prosthetic limb systems.
Experts in both Dr. Schwartz's lab in Pittsburgh and laboratories at Caltech have conducted research using chips with hairlike electrodes to record neurological signatures in the brain. Last year, in an independent effort, Pittsburgh showed that a pair of macaque monkeys with tiny chips implanted in their brains could operate a robotic arm just by thinking about it. Wires carried the signals through the skull, and then computer software converted these signals into robotic arm movements.
As part of the new DARPA work, APL aims to begin implanting spinal cord injury patients in 2011, in collaboration with scientists at the University of Pittsburgh and Caltech.
Volunteers in this study will get two different cortical chips, each carrying 100 recording electrodes. Scientists hope that doubling the capacity to listen to the brain will provide enough independent signals to enable more complex movements on the sophisticated APL arm. "This is a highly dexterous and anthropomorphic arm," says Dr. Schwartz. "The information bandwidth you need to control the device is a lot higher."
The Pittsburgh researchers will also test new chips combined with telemetry systems, which process some of the recorded information on the chip before sending it to a processor implanted in the chest. The processor then wirelessly controls the arm. Current versions in use in humans and monkeys send information via wires coming out of the skull, which increases risk of infection over the long term. While the new setup will be somewhat similar to that used in cardiac pacemakers and deep brain stimulation devices, a prosthetic arm carries out more complex functions than a pacemaker, and therefore more information is needed to control it. "No implantable device has a telemetry system capable of this bandwidth," says Dr. Schwartz. "This technology will be a big step." The Pittsburgh team of researchers ultimately aims to add sensory capability to the arms as well, adding materials that can sense heat and other properties and convey that information to a third chip implanted into part of the brain that processes sensory stimuli.
It's not yet clear what the highest level of complexity will be in terms of controlling the arm. "We're hoping to do at least 11 degrees of freedom," says Dr. Schwartz. His team has developed algorithms that can derive 7 degrees of freedom of movement in monkeys in real time. "How will we move up to 20 or 30? We don't know, maybe we'll need new algorithms, maybe more electrodes," says Dr. Schwartz.
Illustration: This final prototype of the Modular Prosthetic Limb, successfully demonstrated to the Defense Advanced Research Projects Agency in December 2009, offers 22 degrees of motion, including independent movement of each finger. –Johns Hopkins University Applied Physics Laboratory.
In his recent editorial article in the Journal of the American Medical Association, McGowan Institute for Regenerative Medicine affiliated faculty member Derek Angus, MD, MPH, vice chair for research, Department of Critical Care Medicine, University of Pittsburgh Medical Center, and professor in Critical Care Medicine as well as Health Policy and Management at the University of Pittsburgh, noted that sepsis, the syndrome of infection complicated by vital organ dysfunction, is a medical emergency that affects more than 750,000 patients in the United States each year and remains one of the world's leading causes of death. Without prompt resuscitation, antibiotics, and institution of life support, patients can quickly develop shock, multisystem organ failure, and death. It is not surprising, therefore, that the main goal of care and of research has been to reduce short-term mortality. Assuming a patient survives the initial insult, traditional medical wisdom holds that the crisis has been averted and the patient should do well. However, this conventional thinking is being seriously challenged.
According to researchers from the University of Michigan (U-M) Health System, older adults who survive severe sepsis are at higher risk for long-term cognitive impairment and physical limitations than those hospitalized for other reasons. Their research published in the Journal of the American Medical Association showed that 60 percent of hospitalizations for severe sepsis were associated with worsened cognitive and physical function among surviving older adults. The odds of acquiring moderate to severe cognitive impairment were 3.3 times higher following an episode of sepsis than for other hospitalizations.
Severe sepsis was also associated with greater risk for the development of new functional limitations following hospitalization, says the study's lead author, Theodore (Jack) Iwashyna, M.D., Ph.D., assistant professor of internal medicine at U-M. Among patients who had no limitations before sepsis, more than 40% developed trouble with walking. Nearly 1 in 5 developed new problems with shopping or preparing a meal. Patients often developed new problems with such basic things as bathing and toileting themselves.
"We used to think of sepsis as just a medical emergency, an infection that you get sick with and then recover," said Dr. Iwashyna, "But we discovered a significant number of people face years of problems afterwards. Those problems are bigger and more common than we expected. Most older Americans suffer real brain and body problems. We need new treatments, not just for the sepsis infection, but to prevent these new disabilities afterwards." Physicians should use these results in discussing probable outcomes with patients and families, commented Dr. Angus. Longer-term survival and functional outcomes may need to supplant the current main goal of simply getting patients through the acute illness, he suggested.
Reasons for the long-term effects after sepsis might include ICU-acquired weakness thought to be caused by muscle and nerve injury from inflammation and ischemia, as well as by prolonged immobilization and corticosteroid and neuromuscular blockers commonly used in sepsis treatment, Dr. Angus noted. Direct damage to the brain from similar mechanisms as well as encephalopathy and delirium likely also contribute, he added.
Glaucoma is a group of diseases that can damage the eye's optic nerve. It often results in vision loss and blindness. Glaucoma occurs when the normal fluid pressure inside the eyes slowly rises. However, recent findings now show that glaucoma can occur with normal eye pressure. Glaucoma can steal sight without warning signs or symptoms. Patients can often protect their eyes against serious vision loss by treating the disease in its early stages. According to the Glaucoma Research Foundation, more than 4 million Americans have glaucoma, but only 50% know they have it. The suspected number of cases of glaucoma worldwide is 65 million.
In response to these statistics, McGowan Institute for Regenerative Medicine faculty member Joel Schuman, MD, the Eye & Ear Foundation Professor and Chairman, Department of Ophthalmology, University of Pittsburgh, the Director, UPMC Eye Center, and a co-Director of the Louis J. Fox Center for Vision Restoration, and the team of researchers at the Fox Center's Ophthalmic Imaging Research Laboratory are working to:
- improve detection and progression of glaucoma through the use of ocular imaging devices
- develop ocular imaging devices hardware and software for improved diagnostic performance
- enhance the understanding of the ocular pathophysiology, and
- train future vision scientists leaders in ocular imaging.
Dr. Schuman and his colleagues were the first to identify a molecular marker for human glaucoma, as published in Nature Medicine in 2001. He has been continuously funded by the National Eye Institute as a principal investigator since 1995. He is also the principal investigator of a National Institutes of Health (NIH) grant to study novel glaucoma diagnostics. He is co- investigator of NIH grants for research into novel optical diagnostics, short pulse laser surgery, and advanced imaging in glaucoma. Dr. Schuman is an inventor of optical coherence tomography (OCT), used world-wide for ocular diagnostics.
The Ophthalmic Imaging Research Laboratory specializes in the development and testing of cutting edge ophthalmic imaging devices. These devices can assist in the early detection and diagnosis of glaucoma and retinal diseases. The ophthalmic imaging devices provide highly detailed images of ocular structures at micron scale. These devices assist also in the quantification of ocular structures. The Laboratory focuses on the use of ophthalmic imaging devices for glaucoma assessment. Micron-scale imaging leads to an earlier diagnosis and a higher sensitivity in detecting the progression of the disease. These techniques can improve the patient's management of the disease and maintain his/her functional vision.
Recently in OSNSuperSite's Ocular Surgery News U.S. Edition, Dr. Schuman explained his treatment of patients with glaucoma once they are diagnosed. He tells his patients that there are different ways of treating their condition. His first option is eye drops, which have low risk but need to be used every day for the rest of their lives. The most commonly used first-line medication does not have many systemic effects, but it has side effects that are unusual and affect only the eye; these changes may reverse if they were to stop taking the drug.
Dr. Schuman's second option is to use laser therapy. There are risks with this approach as well. Laser therapy works for about 70% of people for at least 1 year, for about 50% of people for 5 years, and for about 30% of people for 10 years. It can be repeated if necessary. Risks include inflammation and swelling of the eye, the pressure can go up instead of down, and there can be scarring in the tissue that is treated. The chance of any of those complications is low, but they can occur.
Glaucoma is mostly an asymptomatic blinding disease. An early and accurate diagnosis is essential to reduce morbidity.
Illustration: National Eye Institute.
McGowan Institute for Regenerative Medicine affiliated faculty member Krzysztof Matyjaszewski, PhD, the J.C. Warner Professor of Natural Sciences at Carnegie Mellon University's Mellon College of Science, is the co-principal investigator of a 3-year, $2.9 million U.S. Department of Defense research grant to develop a therapy that would aid amputees, specifically wounded soldiers. The therapy aims to prevent bone nodules from forming in the muscle at the site of amputation, a painful condition that makes it difficult for amputees to wear limb prostheses.
Amputations among wounded soldiers increased more than 60 percent, from 47 in 2009 to 77 through Sept. 23 of this year, according to U.S. Army reports. The chief causes of amputations are injuries from improvised explosive devices, or IEDs, that are planted in the ground or along roads.
When a limb is amputated, whether by surgical means or as the result of a violent injury, bone can begin to form in the body's soft tissue through a process called heterotopic ossification. Through the new grant, Dr. Matyjaszewski and the team of researchers will develop new tools that will help prevent the growth of these painful bone formations in the muscles of amputees. The bone formations can make it difficult for amputees to wear limb prostheses. In the research program, novel nano-structured polymers will be developed that will place selective biological cues at the stump site to block the bone formation cascade in the soldier's traumatized muscle.
Dr. Matyjaszewski, renowned for developing a method that allows for nanoscale control over the polymers formation, said the ability to control and block mineralization and bone formation opens up many compelling opportunities for increased research. Heterotopic ossification can occur in a number of situations other than amputation, most commonly after joint replacement surgery.
For more than 125 years, pathology has relied on microscopes as its primary tool to determine diagnosis and prognosis. Soon, an integrated digital pathology technology is expected to help enable pathologists to realize the advantages of the digital age like many of their medical peers, such as radiologists.
"Today, studies show an increased need for collaboration in diagnosis in pathology. Given the inherent collaborative limitations of glass slides – the fact that I have to ship it to someone else to review – these consultations with colleagues are difficult, time-intensive, and limited," said McGowan Institute for Regenerative Medicine affiliated faculty member George Michalopoulos, MD, PhD, professor and chairman of the Department of Pathology at the University of Pittsburgh School of Medicine and pathologist at UPMC. "An integrated digital pathology solution will allow pathologists to quickly share cases with the click of a button, increasing collaboration among specialists, and access for rural hospitals."
GE Healthcare and UPMC recently announced that their imaging joint venture, Omnyx™, is initiating clinical research testing of a breakthrough digital pathology platform that is expected to help transform the practice of pathologists using glass slides. By digitizing the slides and corresponding workflow, the Omnyx technology is intended to do what a traditional microscope cannot — unite an entire pathology department and improve collaboration, communication, and efficiency, with the potential for better patient care. Omnyx has initiated research testing of the technology at three sites in the U.S and a fourth in Canada.
The new technology – which will be a truly integrated digital pathology solution – is a combination of patented scanners that boost scan speed by using one camera to scan the slide and a second to simultaneously focus, new imaging software for highest-quality images, and an information technology backbone that digitizes a pathology department's workflow. The digital tools are designed to transform the practice of pathologists using glass slides, microscopes, and manual paperwork to advance patient cases.
An integrated digital pathology solution could help enhance the quality of care for patients by:
- Increasing the efficiency of the pathology process.
- Increasing access by facilitating real-time consultation with specialists, regardless of the patient or specialist's location.
- Facilitating more collaboration among pathologists on patient cases.
UPMC, Montefiore Medical Center, Stanford University Medical Center, and University Health Network are currently installing, testing, and providing feedback on the Omnyx research platform, and will collect data for an FDA clearance submission.
AWARDS AND RECOGNITIONS
The Pittsburgh Section of the American Chemical Society (ACS) has awarded McGowan Institute for Regenerative Medicine Director Alan Russell, PhD, with its 2010 Pittsburgh Award. Dr. Russell, Distinguished University Professor of Surgery, University of Pittsburgh, will receive this honor at a dinner at the Pittsburgh Athletic Association on November 16, 2010.
The Pittsburgh Award was established in 1932 by the Pittsburgh Section of ACS to recognize outstanding leadership in chemical affairs in the local and larger professional community. This Award symbolizes the honor and appreciation accorded to those who have rendered distinguished service to the field of chemistry. Members of the Pittsburgh Section, or in exceptional cases, nonmembers, who have done work worthy of recognition toward increasing chemical knowledge, promoting the chemical industry, benefiting humanity, or advancing the Pittsburgh Section, are eligible for consideration. Nominations for the Pittsburgh Award are solicited from the membership of the Pittsburgh Section.
The award nomination summary reads: Alan J. Russell (PhD in Biological Chemistry, 1987, Imperial College of Science and Technology, University of London) is a Distinguished University Professor of Surgery and the Founding Director of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh.
Further, he holds positions as Professor in the departments of Chemical Engineering and Bioengineering. In addition to his appointments at the University, Dr. Russell is the Executive Director of the Pittsburgh Tissue Engineering Initiative, Inc., as well as a consultant for UPMC's International and Commercial Services Division to drive technology and science-based synergies and partnerships. He has founded three biotechnology companies: ICX Agentase LLC, NanoSembly LLC, and O2Cyte LLC, and is also the Founding President of the 2500-member Tissue Engineering and Regenerative Medicine International Society.
For the last 15 years, the Russell Laboratory has been discovering what can be achieved by exploiting the rich interface of chemistry, biology, and materials. Dr. Russell's work has impacted fields as diverse as chemical and polymer synthesis to tissue engineering and homeland defense. The work began with a detailed study of the structure-function-environment relationship of biological molecules in extreme environments. This work led to an exploration of the use of enzymes in supercritical and ionic fluids. Dr. Russell has pioneered how to make polymers from enzymes and how to incorporate enzymes into bulk polymers. In a series of discoveries Dr. Russell's Laboratory has found how to meld the synthetic and biological worlds.
To date, Dr. Russell has contributed significantly to the interface between the fields of chemistry, biology, and material science. He has given more than 250 national and international invited lectures. Dr. Russell has published 138 articles in refereed journals, 1 book, and 10 book chapters, and holds 14 patents, with 23 additional pending patents.
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Bear DM, Szczodry M, Kramer S, Coyle CH, Smolinski P, Chu CR.
Optical coherence tomography detection of subclinical traumatic cartilage injury.
OBJECTIVES: Posttraumatic arthritis is a major cause of disability. Current clinical imaging modalities are unable to reliably evaluate articular cartilage damage before surface breakdown, when potentially reversible changes are occurring. Optical coherence tomography (OCT) is a nondestructive imaging technology that can detect degenerative changes in articular cartilage with an intact surface. This study tests the hypothesis that OCT detects acute articular cartilage injury after impact at energy levels resulting in chondrocyte death and microstructural changes, but insufficient to produce macroscopic surface damage.
METHODS: Bovine osteochondral cores underwent OCT imaging and were divided into a control with no impact or were subjected to low (0.175 J) or moderate (0.35 J) energy impact. Cores were reimaged with OCT after impact and the OCT signal intensity quantified. A ratio of the superficial to deep layer intensities was calculated and compared before and after impact. Chondrocyte viability was determined 1 day after impact followed by histology and polarized microscopy.
RESULTS: Macroscopic changes to the articular surface were not observed after low and moderate impact. The OCT signal intensity ratio demonstrated a 27% increase (P = 0.006) after low impact and a 38% increase (P = 0.001) after moderate impact. Cell death increased by 150% (P < 0.001) and 200% (P < 0.001) after low and moderate energy impacts, respectively. When compared with unimpacted controls, both Mankin histology and David-Vaudey polarized microscopy scores increased (P = 0.036 and P = 0.002, respectively) after moderate energy impact.CONCLUSIONS: This study shows that OCT detects acute cartilage changes after impact injury at levels insufficient to cause visible damage to the articular surface but sufficient to cause chondrocyte death and microscopic matrix damage. This finding supports the use of OCT to detect microstructural subsurface cartilage damage that is poorly visualized with conventional imaging.
Journal of Orthopaedic Trauma. 2010 Sep;24(9):577-82.
ARM-IV Postdoctoral Program (Four Positions)
10/01/10 – 09/15/12
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