UPMC Physician Resources

Pitt’s Serendipitous Scientific Discovery Holds Potential in Destroying Drug-Resistant Bacteria

Posted by andrewsj3 on Tuesday, May 7th 2013     
PITTSBURGH, May 7, 2013 – Through the serendipity of science, researchers at the University of Pittsburgh have discovered a potential treatment for deadly, drug-resistant bacterial infections that uses the same approach that HIV uses to infect cells.
The National Institutes of Health-supported discovery will be described in the June issue of the journal Antimicrobial Agents and Chemotherapy. It is especially promising in the development of a potential treatment for lung infections in people with cystic fibrosis.
“The discovery of this new antibiotic was an unexpected result of basic research on HIV proteins,” said senior author Ronald Montelaro, Ph.D., professor and co-director of Pitt’s Center for Vaccine Research (CVR). “As a result of studying these proteins, we discovered novel structures that turn out to work very well against bacterial infections, including the complicated bacterial populations in lung infections in cystic fibrosis patients.”
Cystic fibrosis is a genetic disorder that leads to thick, viscous secretions in the lungs and other organs in about 30,000 children and adults in the United States, according to the Cystic Fibrosis Foundation. Lung infections resistant to antibiotics often are deadly for people with cystic fibrosis. About 80 percent of cystic fibrosis patients have at least one antibiotic-resistant infection in their lungs by age 18.
“Infections with progressively resistant bacteria in the lung shorten the lives of people with cystic fibrosis,” said Joseph M. Pilewski, M.D., co-director of the Adult Cystic Fibrosis Center at UPMC. “What happens is the genetic defect predisposes patients to infections that drive the production of mucus that then blocks the airways and makes it difficult to breath.”
Dr. Montelaro and his colleagues found that a particular sequence of amino acids on the tail end of HIV allow the virus to “punch into” and infect cells. The team manufactured a synthetic and more efficient version of this sequence – called engineered cationic antimicrobial peptides, or “eCAPs” – that laboratory tests have shown to rapidly destroy bacteria that are otherwise resistant to most standard antibiotics.
The eCAPs can be assembled in a laboratory setting from the amino acids arginine and tryptophan and manufactured to the shortest effective length, giving the resulting antibiotic treatment maximum potency while reducing costs.
The discovery was featured in April at two prestigious gatherings intended to put scientists in touch with business developers — the BIO International Convention in Chicago, and the University Research & Entrepreneurship Symposium (URES) in Boston.
“At both symposia, we received a lot of interest from pharmaceutical-related companies,” said co-author Jonathan Steckbeck, Ph.D., M.B.A., post-doctoral associate at CVR. “It was a particular honor to be recognized at URES as one of the year’s 10 breakthroughs in life sciences.”
Pitt has taken out several U.S. and international patents on this discovery.
“We have an unmet clinical need for treatment of hospital-acquired infections where the bacteria are extremely resistant to antibiotics,” said co-author Yohei Doi, M.D., Ph.D., assistant professor of medicine in Pitt’s School of Medicine. “We have patients with no treatment options left. The fact that these eCAPs are completely engineered puts them at an advantage because they can be manufactured easily, and they give us some hope for a quick-acting treatment in these dire circumstances.”
Traditional antibiotics typically work by poisoning important metabolic processes after being taken up by the target bacteria, a process that may take hours, or days, to clear a bacterial infection.  In contrast, the eCAPs are specifically attracted to the surface of target bacteria where they disrupt the bacterial membrane, causing death within seconds, or minutes.
Laboratory tests indicate that the eCAPs work well against biofilms, which are bacterial communities that develop very high levels of resistance to antibiotics by working together to protect the film’s inner bacteria from traditional treatments. The eCAPs seem to push through the outer layers of biofilms to destroy the entire bacterial community.
“It’s like a pin bursting a balloon; it’s a very rapid action,” said Dr. Montelaro. “While cystic fibrosis patients are our initial target and a very high-priority target, we also could look at infections associated with burns or indwelling medical devices, such as venous catheters. We could even look to the biodefense realm, in terms of a rapid, handheld nebulizer treatment that soldiers could use in the case of exposure to a bioterrorism agent.”
Additional co-authors are Berthony Deslouches, M.D., Ph.D., and Jodi Craigo, Ph.D., both of Pitt’s Center for Vaccine Research; and Timothy A. Mietzner, Ph.D., of the Lake Erie College of Osteopathic Medicine at Seton Hill.
Funding for this study was provided by NIH award P30CA047904.
Watch the Youtube video of researchers discussing the eCAPs.
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Child Neurodevelopmental and Mental Health Disabilities on the Rise, Children’s Hospital of Pittsburgh of UPMC Study Finds

Posted by andrewsj3 on Sunday, May 5th 2013     

PITTSBURGH, May 5, 2013 – More children have disabilities now than a decade ago, and the greatest increase is among children of higher-income families, according to a Children’s Hospital of Pittsburgh of UPMC study presented today at the Pediatric Academic Societies(PAS) annual meeting in Washington, DC.

Results of the study, led by Amy Houtrow, M.D., Ph.D., M.P.H., chief, Division of Pediatric Rehabilitation Medicine at Children’s Hospital, also showed that while disabilities due to neurodevelopmental and mental health problems have increased sharply, disabilities related to physical health conditions have decreased. This trend was most noteworthy among children under 6 years of age whose rate of neurodevelopmental disabilities nearly doubled during the study, from 19 cases to 36 cases per 1,000 children.

“A century of health care improvements and social changes have altered the face of childhood chronic disease and disability,” said Dr. Houtrow, who also is an associate professor of physical medicine and rehabilitation and of pediatrics at the University of Pittsburgh School of Medicine. “Nearly six  million kids were considered disabled in 2009 and 2010—almost one million more than in 2001 and 2002.”

Dr. Houtrow said that while previous studies have found an increase in the  prevalence of childhood disability, she and the research team wanted to look more closely at the specific conditions and socio-demographic factors associated with disabilities.

The researchers studied data from the National Health Interview Survey conducted by the U.S. Centers for Disease Control and Prevention from 2001 to 2002 and from 2009 to 2010. Participants included  more than 102,000 parents of children up to age 17.

The research team assembled a composite of disability indicators to identify disabled children and their associated underlying chronic conditions. Conditions were categorized into three groups: physical, neurodevelopmental/mental health, and other.

The overall rate of disability for children under age 18 increased 16.3 percent between the 2001 to 2002 study period and the 2009 to 2010 study period.

Children living in poverty represented the largest numbers of overall children with disability in both time periods but not the highest growth rates. The largest increase in growth rates of disabilities was seen among children living in households with incomes at or above 300 percent of the federal poverty level—about $66,000 a year for a family of four in 2010.

“We are worried that children living in lower income families may be having problems accessing diagnostic and treatment services,” Dr. Houtrow said.

Since the study could not pinpoint why the disability rate is increasing, more research is needed, the author concluded.

Co-investigators were: Kandyce Larson, Ph.D., American Academy of Pediatrics; Paul Newacheck, Dr.P.H., Professor of Pediatrics and Health Policy, University of California San Francisco; Neal Halfon M.D., M.P.H., Professor of Pediatrics, Health Policy and Management, UCLA.

For more information on Dr. Houtrow and the Division of Pediatric Rehabilitation Medicine, visit http://www.chp.edu/rehab.

 

 

 

Study Finds Late-Life Depression Associated with Increased Risk for Dementia

Posted by andrewsj3 on Wednesday, May 1st 2013     
PITTSBURGH, May 1, 2013 – Late-life depression is associated with an increased risk for all-cause dementia, Alzheimer’s disease and, most predominantly, vascular dementia, according to the results of a new meta-analysis published today in the British Journal of Psychiatry.
Previous studies have shown an association between depression and Alzheimer’s disease, but this is the first meta-analysis that specifically addresses the risk of Alzheimer’s disease and vascular dementia in older adults with late-life depression.  The study, conducted by researchers at the University of Pittsburgh School of Medicine and the Federal University of Minas Gerais School of Medicine, is also the first to show that late-life depression increases the risk of vascular dementia and that the risk of vascular dementia is greater than the risk of Alzheimer’s disease for older adults with depression.

 

“All-cause dementia” refers to all dementia syndromes, the most common of which is Alzheimer’s disease, accounting for 60 to 80 percent of all dementia cases.  Alzheimer’s disease is associated with memory problems and apathy in early stages, and impaired judgment, confusion, disorientation, behavior changes, and difficulty speaking in later stages.  Vascular dementia is the second most common cause of dementia, and is associated with impaired judgment or ability to plan and complete tasks, as opposed to memory loss that is common in early stages of Alzheimer’s.

 

“An understanding of how late-life depression increases the risk of dementia could lead to better prediction and prevention mechanisms,” said Meryl Butters, Ph.D., associate professor of Psychiatry at the University of Pittsburgh School of Medicine, and corresponding author of the study. “Early diagnosis and prevention of depression could have a major dual public health impact as they could also potentially prevent or delay cognitive decline and dementia in older adults.”
Late-life depression is one of the most common psychiatric illnesses in older adults, affecting 15 percent of adults aged 65+ in the United States, or approximately 6 million people.  Depression in late-life may be a relapse of an earlier depression, or it can be triggered by chronic illness (including degenerative brain diseases such as Alzheimer’s disease), grief, placement in a nursing home, or hospitalization. Late-life depression is associated with poorer general health and higher incidences of cardiovascular disease.

 

Although the symptoms of depression vary, clinical depression is characterized by an inability to function normally or complete daily tasks, over a prolonged period of time.
The research evaluated a total of 23 community-based cohort studies as part of a meta-analysis to calculate the pooled risk of all-cause dementia, Alzheimer’s disease and vascular dementia in older adults with late-life depression.  The findings concluded those with late-life depression are:

 

  • 1.85 times more likely to develop all-cause dementia
  • 1.65 times more likely to develop Alzheimer’s disease
  • 2.52 times more likely to develop vascular dementia

The authors note that preventing depression and improving general health including cardiovascular health should be considered in public health policies associated with preventing and/or delaying the onset of dementia.

“Fortunately, we already know that depression can be prevented and treated,” added Dr. Butters. “Now that we know the risks of dementia, we need to conduct clinical trials to investigate the impact of preventing depression on risk of cognitive decline and dementia in older adults.”

This research was sponsored by the National Institute of Mental Health (NIMH) and the John A. Hartford Foundation Center of Excellence in Geriatric Psychiatry at UPMC.

 

Pitt Team Finds Melatonin Delays ALS Symptom Onset and Death in Mice

Posted by andrewsj3 on Thursday, April 25th 2013     
PITTSBURGH, April 25 – Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study by researchers at the University of Pittsburgh School of Medicine. In a report published online ahead of print in the journal Neurobiology of Disease, the team revealed that receptors for melatonin are found in the nerve cells, a finding that could launch novel therapeutic approaches.
 
Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles, said senior investigator Robert Friedlander, M.D., UPMC Endowed Professor of neurosurgery and neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But the causes of the condition are not well understood, thwarting development of a cure or even effective treatments.
 
Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than a thousand FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.
 
“Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS,” Dr. Friedlander said. “We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases.”
 
Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer, and had less degeneration of motor neurons in the spinal cord.
 
“Much more work has to be done to unravel these mechanisms before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment,” Dr. Friedlander said. “I suspect that a combination of agents that act on these pathways will be needed to make headway with this devastating disease.”
 
Co-authors of the paper include other scientists from the University of Pittsburgh School of Medicine; Harvard Medical School; Ohio State University; Weifang Medical University; Bedford VA Medical System, Boston; St. Joseph’s Hospital and Medical Center, Phoenix; University of Texas Medical School at Houston; and VA Pittsburgh Health Care System.
 
The project was funded by grants NS051756, NS039324, and NS055072 of the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health; the U.S. Department of Defense; and the Muscular Dystrophy Association.

Mild Blast Injury Causes Molecular Changes in Brain Akin to Alzheimer’s Disease, Pitt-Led Team Says

Posted by andrewsj3 on Wednesday, April 24th 2013     
PITTSBURGH, April 24 – A multicenter study led by scientists at the University of Pittsburgh School of Medicine shows that mild traumatic brain injury after blast exposure produces inflammation, oxidative stress and gene activation patterns akin to disorders of memory processing such as Alzheimer’s disease. Their findings were recently reported in the online version of the Journal of Neurotrauma.
 
Blast-induced traumatic brain injury (TBI) has become an important issue in combat casualty care, said senior investigator Patrick Kochanek, M.D., professor and vice chair of critical care medicine and director of the Safar Center for Resuscitation Research at Pitt. In many cases of mild TBI, MRI scans and other conventional imaging technology do not show overt damage to the brain.
 
“Our research reveals that despite the lack of a lot of obvious neuronal death, there is a lot of molecular madness going on in the brain after a blast exposure,” Dr. Kochanek said. “Even subtle injuries resulted in significant alterations of brain chemistry.”
 
The research team developed a rat model to examine whether mild blast exposure in a device called a shock tube caused any changes in the brain even if there was no indication of direct cell death, such as bleeding. Brain tissues of rats exposed to blast and to a sham procedure were tested two and 24 hours after the injury.
 
Gene activity patterns, which shifted over time, resembled patterns seen in neurodegenerative diseases, particularly Alzheimer’s, Dr. Kochanek noted. Markers of inflammation and oxidative stress, which reflects disruptions of cell signaling, were elevated, but there was no indication of energy failure that would be seen with poor tissue oxygenation.
 
“It appears that although the neurons don’t die after a mild injury, they do sustain damage,” he said. “It remains to be seen what multiple exposures, meaning repeat concussions, do to the brain over the long term.”
Co-authors include researchers from the Safar Center for Resuscitation Research and the University of Pittsburgh School of Medicine; University of California, San Diego; ORA Inc., of Fredericksburg, Va.; Walter Reed Army Institute of ResearchDyn-FX Consulting Ltd, Amherstburg, ON; Uniformed Services University of the Health Sciences, Bethesda, MD; and Integrated Services Group, Inc., Potomac, MD.
 
The project was funded by the Defense Advanced Research Projects Agency.

Recipe for Making Large Numbers of Stem Cells Requires Only One Ingredient, says NIH/Pitt Team

Posted by andrewsj3 on Wednesday, April 17th 2013     

PITTSBURGH, April 17, 2013 – Stem cells and tissue-specific cells can be grown in abundance from mature mammalian cells simply by blocking a certain membrane protein, according to scientists at the University of Pittsburgh School of Medicine and the National Institutes of Health (NIH). Their experiments, reported today in Scientific Reports, also show that the process doesn’t require other kinds of cells or agents to artificially support cell growth and doesn’t activate cancer genes.

Scientists  hope lab-grown stem cells and induced pluripotent stem (iPS) cells, which have the ability to produce specialized cells such as neurons and cardiac cells, could one day be used to treat diseases and repair damaged tissues, said  co-author Jeffrey S. Isenberg, M.D., associate professor, Division of Pulmonary, Allergy and Critical Care Medicine, Pitt School of Medicine.

“Even though stem cells are able to self-renew, they are quite challenging to grow in the lab,” he said. “Often you have to use feeder cells or introduce viral vectors to artificially create the conditions needed for these cells to survive and thrive.”

In 2008, prior to joining Pitt, Dr. Isenberg was working in the National Cancer Institute (NCI) lab of senior author David D. Roberts, Ph.D., using agents that block a membrane protein called CD47 to explore their effects on blood vessels. He noticed that when cells from the lining of the lungs, called endothelium, had been treated with a CD47 blocker, they stayed healthy and maintained their growth and function for months.

Dr. Roberts’ NIH team continued to experiment with CD47 blockade, focusing on defining the underlying molecular mechanisms that control cell growth.

They found that endothelial cells obtained from mice lacking CD47 multiplied readily and thrived in a culture dish, unlike those from control mice. Lead author Sukhbir Kaur, Ph.D., discovered that this resulted from increased expression of four genes that are regarded to be essential for formation of iPS cells. When placed into a defined growth medium, cells lacking CD47 spontaneously formed clusters characteristic of iPS cells. By then introducing various growth factors into the culture medium, these cells could be directed to become cells of other tissue types. Despite their vigorous growth, they didn’t form tumors when injected into mice, a major disadvantage when using existing iPS cells.

“Stem cells prepared by this new procedure should be much safer to use in patients,” Dr. Roberts noted. “Also, the technique opens up opportunities to treat various illnesses by injecting a drug that stimulates patients to make more of their own stem cells.”

According to Dr. Isenberg, “These experiments indicate that we can take a primary human or other mammalian cell, even a mature adult cell, and by targeting CD47 turn on its pluripotent capability. We can get brain cells, liver cells, muscle cells and more. In the short term, they could be a boon for a variety of research questions in the lab.”

In the future, blocking CD47 might make it possible to generate large numbers of healthy cells for therapies, such as alternatives to conventional bone marrow transplantation and complex tissue and organ bioengineering, he added.

“These exciting findings provide a rationale for using CD47 blocking therapies to increase stem cell uptake and survival in transplanted organs, matrix grafts, or other applications,” said Mark Gladwin, M.D., professor and chief, Division of Pulmonary, Allergy and Critical Care Medicine, Pitt School of Medicine. “This continues a strong and productive collaboration between investigators at the NCI and the University of Pittsburgh’s Vascular Medicine Institute.”

Co-authors of the paper include David R. Soto-Pantoja, Ph.D., Michael L. Pendrak, Ph.D., Alina Nicolae, M.D., Ph.D., Zuqin Nie, Ph.D., and David Levens, M.D., Ph.D., of the National Cancer Institute (NCI); Erica V. Stein, B.S., M.Ed., of NCI and George Washington University; Chengyu Liu, Ph.D., of the National Heart, Lung and Blood Institute; Abdel G. Elkahloun, Ph.D., of the National Human Genome Research Institute (NHGRI); and Satya P. Singh, Ph.D., of the National Institute of Allergy and Infectious Diseases.

The project was funded by the NIH, NCI and NHGRI intramural programs and grants HL108954-01, HL103455-01, 11BGIA7210001; the Institute for Transfusion Medicine, the Western Pennsylvania Hemophilia Center, and Pitt’s Vascular Medicine Institute.

Children’s Hospital of Pittsburgh of UPMC Study Reveals Success Rate of Minimally Invasive Surgical Approaches in Infants

Posted by andrewsj3 on Wednesday, April 10th 2013     
PITTSBURGH, April 10, 2013 – Blockage between the kidney and the ureter in infants can be successfully repaired with minimally invasive surgical approaches, according to a Children’s Hospital of Pittsburgh of UPMC study. The findings are published in the April issue of The Journal of Urology.
 
Ureteropelvic junction (UPJ) obstruction is the most common obstructive urinary system disease in infants, according to senior investigator Michael Ost, M.D., chief, Division of Pediatric Urology at Children’s Hospital. The problem typically has been repaired with a procedure called pyeloplasty, in which an incision is made in the infant’s side to reach and remove scar tissue where the kidney meets the ureter, the tube that carries urine to the bladder.
 
The minimally invasive approach – called transperitoneal laparoscopic pyeloplasty, which can also be done with robot assistance – has emerged as a safe, effective alternative to the standard open pyeloplasty. Both laparoscopic and open pyeloplasty have comparable effectiveness in pediatric patients, but the role of infants is less well defined.
 
“This population can be challenging to treat laparascopically because of the small size of the abdomen and caliber of the ureter,” Dr. Ost said.
 
His team reviewed records of 29 children younger than 12 months old treated with transperitoneal laparoscopic pyeloplasty for UPJ obstruction from May 2005 to February 2012. Of the 24 patients for whom follow-up data was available, 22 (92 percent) had successful repairs. Two patients required a second, open procedure to correct the obstruction.
 
“Our results show the laparoscopic approach is a safe and effective option for the surgical management of UPJ obstruction in the infant population,” said Dr. Ost. “Our early experience reveals a developing success rate comparable to that of other treatment modalities with minimal morbidity.”
 
Children’s is a national leader in minimally invasive procedures, having performed more than 1,000 such surgeries in the last year. So far in fiscal year 2013, Children’s surgeons have performed more than 760 MIS operations.
 
Children’s is also one of just a handful of pediatric hospitals in the world that features the top-of-the-line surgical robot system, called the daVinci SI Dual Consol Surgical System. The technology allows Children’s surgeons to perform some minimally invasive procedures that in the past couldn’t be performed laproscopically. Increasingly complex, delicate operations can be done through very small surgical openings by specially trained surgeons through the use of the daVinci. Growth in robotic procedures has increased markedly across surgical services.
 
For more information on Dr. Ost and to learn more about minimally invasive and robotic-assisted surgeries at Children’s Hospital, please visit http://www.chp.edu/minimally+invasive+surgery.

Pitt Team Finds Protein That Ramps Up Inflammation, and Agents That Can Block It

Posted by andrewsj3 on Monday, April 1st 2013     

Could Improve Treatments for Pneumonia and Other Inflammatory Conditions

PITTSBURGH, April 1, 2013 – Scientists at the University of Pittsburgh School of Medicine discovered a new biological pathway of innate immunity that ramps up inflammation and then identified agents that can block it, leading to increased survival and improved lung function in animal models of pneumonia. They reported their findings today in Nature Immunology.
 
Pneumonia and other infections sometimes provoke an inflammatory response from the body that is more detrimental than the disease-causing bacteria, said senior author Rama Mallampalli, M.D, professor and vice chair for research, Department of Medicine, and director of the Acute Lung Injury Center of Excellence at Pitt.
 
“In our ongoing studies of pneumonia, we found infecting bacteria activate a previously unknown protein called Fbxo3 to form a complex that degrades another protein called Fbxl2, which is needed to suppress the inflammatory response,” said Dr. Mallampalli, who is also chief of the pulmonary division of the VA Pittsburgh Healthcare System. “The result is an exaggerated inflammatory response that can lead to further damage of the lung tissue, multi-organ failure and shock.”
 
The research team, led by Bill B. Chen, Ph.D., associate professor, Division of Pulmonary, Allergy and Critical Care Medicine (PACCM), conducted experiments in which mice that lacked the ability to make Fbxo3 were infected with a strain of Pseudomonas bacteria, and found that they had better lung mechanics and longer survival than mice that still made the protein.
 
Research team members Bryan J. McVerry, M.D., and Yingze Zhang, Ph.D., both of the Acute Lung Injury Center of Excellence, found that blood samples from 16 people who had sepsis, a condition of systemic inflammation, revealed higher levels of Fbxo3 –- along with other inflammatory proteins — and lower levels of Fbxl2 than samples from seven patients who did not have sepsis or lung infection.
Based on the structure of Fbxo3, the researchers developed a family of small molecules with the aim of inhibiting its activity. Administration of one of them, called BC-1215, led to reduced inflammatory markers and improved lung mechanics in mouse models of pneumonia and sepsis.
 
“The key is to find ways to help the body temper its inflammatory response so that it’s able to kill the infectious agent without causing injury to healthy tissue,” Dr. Mallampalli said.
 
“The F-box protein Fbxo3, and other related proteins, represent ideal targets for treatment of acute lung injury, because it controls the innate immune response, is upstream of important inflammatory signaling pathways, and is more selective than traditional drugs that regulate protein turnover,” noted Mark T. Gladwin, M.D., the PACCM chief.
 
The team is beginning to study the effects of BC-125 on other conditions of systemic inflammation, such as colitis and arthritis.
 
Co-authors of the paper include Tiffany A. Coon, Jennifer R. Glasser, Jing Zhao, Ph.D., Yutong Zhao, M.D, Ph.D., Chunbin Zou, Ph.D, Bryon Ellis, and Frank C. Sciurba, M.D., all of the Acute Lung Injury Center of Excellence, University of Pittsburgh.
 
The study was funded by the U.S. Department of Veterans Affairs; National Institutes of Health grants HL096376, HL097376, HL098174, HL116472, HL01916, and P50HL084948; and the American Heart Association.

Pitt, Mount Sinai Team Finds Novel Mechanism Regulating Replication of Insulin-Producing Beta Cells for Diabetes Treatment

Posted by andrewsj3 on Tuesday, March 26th 2013     
PITTSBURGH / NEW YORK, March 26, 2013 – Bringing scientists a step closer to new treatments for diabetes, researchers at the University of Pittsburgh School of Medicine and The Mount Sinai Medical Center have discovered a novel mechanism that regulates the replication of insulin-producing beta cells in the pancreas. The findings were recently published online ahead of print in Diabetes, a journal of the American Diabetes Association.
Regenerating beta cells to restore insulin production has moved to center stage in the quest for therapies for both Type 1 and 2 diabetes, said lead author Nathalie Fiaschi-Taesch, Ph.D., assistant professor, Division of Endocrinology and Metabolism, Pitt School of Medicine.
“Ideally, we would be able to do this by collecting cells from donor pancreatic tissue and growing them in the lab or better yet, giving a patient a pill to stimulate their own beta cells to replicate,” she said. “In the past, this has proven to be very challenging. Our findings provide new insights into how one may be able to do this. ”
After a 2009 paper in which a team led by Dr. Fiaschi-Taesch and Andrew F. Stewart, M.D., formerly of Pitt and now Irene and Dr. Arthur M. Fishberg Professor of Medicine and director of the Diabetes, Obesity and Metabolism Institute at The Mount Sinai Medical Center in New York, successfully induced human beta cells to replicate in the lab by elevating the level of a protein called cdk-6.  In two current reports in Diabetes, they continued to examine the workings of the cell cycle proteins involved in the replication machinery.
What they found surprised them. Scientists had assumed the proteins resided in the cell’s nucleus, where they could act upon genes and molecules to stimulate – or in the case of beta cells, prevent – cell replication. Their experiments showed that the cell cycle proteins were actually in the cell’s cytoplasm, the fluid around the nucleus and contained within the cell membrane.
“It’s like looking under the hood of a car for the engine and instead finding all the parts scattered around the back seat: it’s no wonder the car won’t go,” Dr. Stewart explained. “Now we have to find ways to get those parts hooked up and back under the hood so that they can once again function as the engine that drives beta cell replication.”
Increasing levels of cdk-6 led that molecule and other key (or critical) cell cycle proteins to move into the nucleus to foster replication, but in the quiescent or non-replicating cell, the only ones that remained in the nucleus were inhibitors of replication. Understanding how and why those inhibiting proteins block replication could in turn lead to ways to block their activity, providing a novel approach for reviving beta cell regeneration, Dr. Fiaschi-Taesch said.
Dr. Stewart noted that the relocation of cell cycle proteins outside the nucleus in the beta cell might hold true for other kinds of cells.
“It makes me curious about whether we can turn replication back on in other cells that aren’t known to regenerate, such as neurons,” he said. “I’d also like to know why these proteins continue to be produced by the quiescent cell if they aren’t playing a role in cell replication.”
In the second Diabetes paper, the team described the intracellular localization of all the cell cycle proteins in the beta cell, a biochemical atlas that could guide other researchers.
Co-authors include Jeffrey W. Kleinberger, B.S., Fatimah Salim, B.S., Ronnie Troxell, B.S., Rachel Wills, B.S., Mansoor Tanwir, M.D., Gabriella Casinelli, B.S., Amy E. Cox, M.D., and Karen K. Takane, Ph.D., Harish Srinivas, Ph.D., all of the Division of Endocrinology and Metabolism, Pitt School of Medicine; and Donald K. Scott, Ph.D., of Mount Sinai Medical Center.
The project was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, though grants U-01 DK 089538, R-01 DK55023, R56 DK065149 and T32-07052; the Juvenile Diabetes Research Foundation; the American Diabetes Association, and the University of Pittsburgh.

UPMC Eye Center to Present at ARVO Annual Meeting

Posted by UPMC Physician Resources on Friday, March 22nd 2013     

Joel S. Schuman, MD, FACS, director, UPMC Eye Center, and other researchers from the UPMC Eye Center will present on a variety of topics at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). The meeting will take place May 5 to 9 in Seattle, WA.

Dr. Schuman, along with Gadi Wollstein, MD will lead a cross-sectional group discussion on technological advances in optical coherence tomography. They will explain how tools and procedures such as scanning laser ophthalmoscopy and photoacoustic ophthalmoscopy are now used in imaging and how functional measurements such as ocular blood flow and oxygen tension are currently used in In Vivo investigation.

In addition, Ian Sigel, PhD, will present on two topics entitled, “Optic Nerve Head Biometrics” and “IOP Elevation Reduces the Waviness of the Load Bearing Collagen Fibers in the Lamina Cribosa.

Attendees also are invited to join the UPMC Eye Center at the annual Alumni and Friends reception where they will congratulate Dr. Schuman, who was a co-recipient of the 2012 Champalimaud Award. The reception is scheduled for Friday, May 4, at 7 p.m., at the Fairmont Hotel Seattle. Please email Lauren Wally or call (412) 864-3283 for more information or to RSVP.

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