Bench to Bedside

March 2014

Blood Pressure Signals Could Offer Drug Targets


The list of genes affecting blood pressure is expanding, as researchers pursue likely targets for therapeutics already in existence or in development. A Children’s Hospital researcher collaborated with an international study team that discovered 11 novel genetic signals associated with blood pressure levels and confirmed 27 previously discovered genetic signals.

High blood pressure, or hypertension, is a complex condition and a well-known risk factor for heart disease, stroke, peripheral artery disease, and chronic kidney disease. A substantial need for improved blood pressure medicines exists because not all patients respond well to current treatments, and other patients require combinations of three or more drugs.

Most of the new genetic signals that Brendan J. Keating, DPhil, a geneticist with The Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia, and the study’s co-authors identified are “druggable” targets that offer the possibility of expedited pharmaceutical development of therapeutics for high blood pressure.

“Some of the protein targets already are targets of existing drugs for other diseases, while others are the focus of drugs currently in early-phase clinical trials or under preclinical development,” Dr. Keating said.

In the study that appeared online in the American Journal of Human Genetics, the researchers performed a discovery analysis of DNA from more than 87,000 individuals of European ancestry. They assessed their initial findings in a replication test, using an independent set of another 68,000 individuals.

The researchers then used pharmacological databases to analyze potential targets in the discovered genetic region. They found that gene products associated with 10 of the genes were predicted to be targets for small-molecule drugs. In fact, two genes — KCNJ11 and NQO1 — are currently targeted by existing approved drugs.

“If clinicians can reposition existing drugs to treat some patients with hypertension, this will save significant time in drug development, as they won’t be starting development from scratch,” Dr. Keating said.

He added that even with possible repositioning, more research is needed to determine which drug candidates are effective against hypertension, possibly in personalized treatments based on patients’ genetic makeup.

Dr. Keating is the lead clinical data analyst at CAG, one of the world’s largest programs for detecting gene variations and linking them to particular illnesses, and the only such program entirely based at a pediatric hospital. In addition to his position at CHOP, Dr. Keating is a faculty member of the Department of Pediatrics and the Division of Transplantation in the Department of Surgery in the Perelman School of Medicine at the University of Pennsylvania.

For this study, Dr. Keating collaborated with two senior co-authors, Folkert W. Asselbergs, MD, PhD, of University Medical Center Utrecht, the Netherlands, and Patricia B. Munroe, PhD, of Queen Mary University, London, U.K. Other study co-authors were from the U.S., the U.K., the Netherlands, Canada, Germany, Sweden, and Ireland.

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Study Reports Preterm Infant Tracheostomy Outcomes


Neonatologists at The Children’s Hospital of Philadelphia frequently face the difficult decision of whether to place a tracheostomy in a preterm infant with severe lung disease and when to do it. But a lack of relevant literature about this procedure can make it a challenging consideration.

However, a recent study in the Journal of Pediatrics led by a CHOP neonatologist offers further guidance on this problem by evaluating the developmental outcomes of infants born before 30 weeks’ gestation who underwent tracheostomy. With these data in hand, clinicians contemplating a tracheostomy for a preterm infant can supplement clinical status and medical history to help parents comprehend potential long-term outcomes.

Premature infants’ lungs, especially the air sacs, are not fully developed. While many premature infants must use a mechanical ventilator and extra oxygen for breathing, a minority ultimately undergo tracheostomy placement. A tracheostomy is the insertion of an artificial airway into the windpipe through a surgical incision to provide a safe, long-term way to ventilate a child.

When a team led by Sara B. DeMauro, MD, MSCE, an attending neonatologist and medical director of Neonatal Follow-up Programs at CHOP, looked at a dataset collected at 16 sites from 2001 to 2011 by the NICHD Neonatal Research Network, they identified 304 preterm infants with tracheostomies to include in a retrospective cohort study.

“This is the first time anybody has ever performed a comprehensive evaluation of the developmental outcomes of these children at 18-22 months,” Dr. DeMauro said.

The researchers demonstrated that even when they performed adjusted analyses controlling for many of the factors known to be predictive of poor developmental outcomes in preterm infants, those with tracheostomies still had significantly increased odds of adverse outcomes. These outcomes consisted of neurologic impairment, developmental delay, or visual or hearing impairment. Dr. DeMauro pointed out that while this study suggests that tracheostomy is a marker for a risk of adverse developmental outcomes in this vulnerable population, it does not indicate that tracheostomy causes these problems.

“Based on their entire medical histories, these children are predisposed to having poor developmental outcomes,” Dr. DeMauro said. “This is almost a way to measure that. If they’re so sick that they need a tracheostomy, then they’re so sick that they’re at very high risk for having an adverse outcome.”

This clinical conundrum has another nuance: If a preterm infant needs a tracheostomy, when should the procedure be performed?

Again, Dr. DeMauro and colleagues found a paucity of literature to guide that decision. So they assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life. Their study suggests a possible association between earlier tracheostomy and better neurodevelopmental outcomes.

While more studies must be done to determine if earlier decisions about tracheostomy placement are advantageous, Dr. DeMauro described how it is possible that a “sooner than later” approach could have benefits in the NICU.

“Before their tracheostomy is placed, infants aren’t allowed to move around too much because they could dislodge their tube. Therefore, they can’t engage in developmentally appropriate play and are often heavily sedated,” Dr. DeMauro said. “As soon as they have a tracheostomy that is in place and healed, you get them out of bed, you play with them, and you take them off sedation.”

Further data also is needed on the outcomes of tracheostomy in preterm infants who have lung disease compared to those who also have airway disease. Delving into these complexities will help clinicians have more complete information when they speak with families about pursuing tracheostomy placement, Dr. DeMauro said.

“This study is an important first step in understanding what the range of outcomes for these children tends to be,” she said. “When these data are combined with a child’s individual clinical situation and any additional risk factors for poor outcomes, it allows you to make a much more informed decision about whether a tracheostomy is a good choice.”

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Retinopathy of Prematurity Associated With Disabilities


A study led by a CHOP neonatology expert showed that infants with severe retinopathy of prematurity (ROP) diagnosed and treated under modern protocols remain at risk of nonvisual disabilities, even if blindness can be averted in most children.

ROP is a disorder of the blood vessels of the retina, which are not completely developed until a baby reaches full term. A baby born prematurely may have growth of abnormal blood vessels, or damage and scarring of existing blood vessels in the retina. This can lead to retinal scarring or detachment from the back of the eye, resulting in vision loss.

Severe ROP is not a rare condition, and its incidence has been rising. It occurs in at least 10 percent of unselected and extremely preterm infants — those born at less than 29 out of 40 weeks of gestation. Moreover, it is a serious problem in middle-income countries where even moderately preterm babies are affected.

“It is therefore important to research the association between this neonatal complication and adverse long-term child development,” said Barbara Schmidt, MD, MSc, an attending neonatologist at The Children’s Hospital of Philadelphia and professor of pediatrics and the Kristine Sandberg Knisely Chair in Neonatology at the Perelman School of Medicine at the University of Pennsylvania.

This exploratory analysis reported in the Journal of the American Medical Association used data from a cohort of very low-birth-weight infants involved in the Caffeine for Apnea of Prematurity trial. Study participants included 1,582 children born at 31 centers between 1999 and 2004 and followed up at age 5. Of the 95 children who had severe ROP, 12 were bilaterally blind at 5 years. The study found that motor impairment, cognitive impairment, and severe hearing loss were three to four times more common in children with severe ROP than those without severe ROP.

These findings remind clinicians and parents that while blindness often can be prevented by timely retinal therapy in the neonatal intensive care unit, severe ROP remains a predictor of functional disability. It reinforces the need for long-term visual and developmental follow-up for infants who are diagnosed with severe ROP. Yet it remains unclear why there is an association between the development of severe ROP and the presence of nonvisual disabilities.

“We can only speculate,” Dr. Schmidt said. “The retina has been called a ‘window to the brain;’ hence, severe damage to the developing retina in a very immature baby may also indicate damage to the developing brain.”

Future studies could examine whether the association that investigators observed between severe ROP and nonvisual disability represents a “cause and effect” relationship. Dr. Schmidt also suggested that more research on effective strategies in the neonatal intensive care unit to prevent severe ROP is needed.

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Donation Creates Penn, CHOP Center of Excellence


Three longtime allies have joined forces to create the new Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence. The establishment of the center was catalyzed by a $3.25 million gift from the Friedreich’s Ataxia Research Alliance (FARA), in partnership with the Hamilton and Finneran families.

Friedreich’s ataxia (FA) is a progressive neurogenetic condition found in approximately 1 in 50,000 people worldwide. While relatively rare, it is the most common form of inherited ataxia, a condition characterized by progressive lack of coordinated movement and loss of balance. FA also involves degeneration of heart muscle and nerve cells. Symptoms usually begin in childhood, and most patients are confined to a wheelchair by their mid-to-late twenties. Myocardial failure and/or arrhythmias are the most common cause of premature death. Currently there are no approved drugs to treat FA.

For the past 16 years Penn Medicine, The Children’s Hospital of Philadelphia, and FARA, a nonprofit organization dedicated to curing FA, have worked together to provide and advance the care needed by FA patients.

FARA, CHOP, and Penn Medicine have also shared in research and clinical trials that have elucidated the metabolic dysfunction underlying FA. Their work has created a database of well-documented patients and a pipeline of more than 20 drug candidates ready to be mined for new therapies. Today the FA clinical program at CHOP is the largest in the world.

The new Center’s team is working with pharmaceutical industry partners to develop drug candidates as well as biomarkers for FA, and this effort fits alongside a broader initiative at Penn Medicine, as a gift from an anonymous donor recently founded the Center for Orphan Disease Research and Therapy to support the pursuit of novel therapies for rare diseases of all kinds.

The Friedreich’s Ataxia Center of Excellence is co-directed by David Lynch, MD, PhD, FA program director at CHOP, and Robert B. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine at the Perelman School of Medicine. Drs. Lynch and Wilson both serve on FARA’s Scientific Advisory Board, and Dr. Wilson was a founding member of FARA’s board of directors and first chairman of its Scientific Review Committee.

The early goals and objectives of the Center include:

“Integrating cardiac expertise into the care of patients is one major step forward this gift allows us to pursue,” says Philip R. Johnson, MD, executive vice president and chief scientific officer at CHOP. “Rare diseases are often an area where philanthropy can make a difference, and the generosity of these donors will make a significant impact.”

Additional information about the new Friedreich’s Ataxia Center of Excellence is available here.

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Genetic Signals Linking Weight, Heart Risk Factors Found


Two recent studies, both co-led by The Children’s Hospital of Philadelphia’s Brendan J. Keating, DPhil, expand the list of genes involved with body fat and body mass index, and their connection to heart disease, high blood pressure, and diabetes.

One study, published in the American Journal of Human Genetics, showed that higher body mass index (BMI) caused harmful effects on the risk of type 2 diabetes, high blood pressure, and inflammation. Meanwhile a second study, published in Human Molecular Genetics, found gene signals linked to higher levels of body fat metrics.

According to the CDC, heart disease causes approximately 600,000 deaths each year in the United States, and 67 million adults have high blood pressure (which is associated with increased rates of heart attack, heart failure, and stroke). For its part, diabetes is the seventh most common cause of death, and nearly 12 percent of American adults over 20 years of age are living with diabetes.

“These findings are highly relevant to the obesity pandemic in the United States and many other countries,” said the Center for Applied Genomics’ Dr. Keating. “Of course, much research remains to be performed to discover further genes involved in these complex metabolic diseases, and to better understand how to improve treatments.”

Lowering BMI Could Improve Cardiovascular Health

In the American Journal of Human Genetics BMI investigation, Dr. Keating collaborated with clinical epidemiologist Michael V. Holmes, MD, PhD, of the Perelman School of Medicine at the University of Pennsylvania. That study made use of a recently developed epidemiology tool called Mendelian randomization (MR) that rules out confounding factors such as behavioral and environmental influences to construct genetic risk scores for specific traits of interest.

The study team analyzed eight population cohorts including more than 34,000 individuals of European descent, of whom over 4,400 had type 2 diabetes, more than  6,000 had coronary heart disease and more than  3,800 had a previous stroke.

The authors concluded that their analysis supports the importance of BMI in regulating cardiometabolic traits and the risk of type 2 diabetes. “Our findings suggest that lowering BMI is likely to result in multiple reductions of cardiovascular traits: in blood pressure, inflammation, fasting glucose and insulin, and in the risk of type 2 diabetes,” said Dr. Keating.

“This study is the first to use this emerging MR technique with a combination of genetic markers known to impact BMI, to assess the causal relationship of BMI and a comprehensive repertoire of traits,” said Dr. Holmes. Although the study showed that increasing BMI has an undesirable effect on cardiometabolic factors, interestingly, it did not show that higher BMI increased the risk of coronary heart disease, Dr. Holmes added.

Body Fat Genetic Signals Discovered

Dr. Keating also co-led a second study, published recently in Human Molecular Genetics, analyzing genes associated with central adiposity. Measures of central adiposity, or body fat, can be derived using waist circumference and waist-to-hip ratio. “For assessing the influence of weight-related genes, central adiposity is preferable to BMI, because BMI also reflects the influence of genes affecting height,” said Dr. Keating.

Keating’s co-senior author was Kira C. Taylor, PhD, MS, of the University of Louisville. The study team performed a meta-analysis in over 57,000 subjects of European ancestry, then validated their results in even larger numbers from independent studies.

This study discovered three novel genetic signals associated with central adiposity, in the genes TMCC1, HOXC10, and PEMT. In addition, the team found two more novel genetic signals, in the SHC1 and ATBDB4 genes, which were only observed in women.

“Previous research has reported different gene variants operating between men and women related to adiposity,” said Dr. Keating. “This gives us initial clues of the genes involved with sex-specific body shapes. Future research using these findings may yield insight into the actual biological mechanisms that dictate why males and females have different body distributions of fat deposits.”

The adiposity study showed an association, not a causal role, for the genetic signals, with other signals yet to be discovered using even larger sample sizes. Several of the genes are in regulatory regions, Dr. Keating noted. While additional work is needed to tease out the biology of these signals, but the first steps of identifying genes underpinning these traits has been accomplished, Dr. Keating added.

For more information about both studies, see the full press release.

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As One Food Allergy Resolves, Another May Develop


Some children who outgrow one type of food allergy may then develop another type of allergy, more severe and more persistent, to the same food. A new study by pediatric allergy experts suggests that healthcare providers and caregivers carefully monitor children with food allergies to recognize early signs of eosinophilic esophagitis (EoE), a severe and often painful type of allergy that has been increasing in recent years.

“These two types of allergy have some elements in common, but patients with EoE usually don’t go on to develop tolerance to the foods that trigger EoE,” said pediatric allergist Jonathan M. Spergel, MD, PhD. Dr. Spergel directs CHOP’s Center for Pediatric Eosinophilic Disorders, one of the nation’s premier programs for these conditions.

Only recently recognized as a distinct condition, EoE involves swelling and inflammation of the esophagus, along with excessive levels of immune cells called eosinophils. Often painful, EoE may cause weight loss, vomiting, heartburn, and swallowing difficulties. EoE can affect any age group, but it is often first discovered in children experiencing feeding difficulties and failure to thrive.

Dr. Spergel’s team compared EoE with IgE-mediated food allergy — the more familiar type of food allergy that occurs when antibodies mount an exaggerated immune response against proteins in particular foods. Nuts, eggs, or milk, for example, may trigger hives, other skin reactions, vomiting, or other symptoms.

The researchers performed a retrospective analysis of all children seen at CHOP for EoE between 2000 and 2012, a total of 1,375 patients. Of that number, 425 researchers identified a definite food causing their condition — most commonly milk, egg, soy, and wheat. Within that subgroup, 17 patients had developed EoE to a food after having outgrown IgE-mediated allergy to that specific food.

“The pattern we found in those 17 patients suggests that the two types of food allergy have distinct pathophysiologies — they operate by different mechanisms and cause different functional changes,” Dr. Spergel said. “However, this pattern also raises the possibility that prior IgE-mediated food allergy may predispose a patient to developing EoE to the same food.”

Dr. Spergel added that approximately 10 percent of patients who undergo desensitization therapy for IgE-mediated foods allergies subsequently develop EoE to the same food — a fact that healthcare providers should consider in managing care for patients with food allergies. In desensitization therapy, a clinician exposes a patient to miniscule amount of an allergy-producing food, then gradually increases the amount, aiming for the patient to become tolerant to that food.

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Paper Explores Endoplasmic Reticulum Stress Response


By shedding light on how cells deal with stress, a new study led by The Children’s Hospital of Philadelphia’s Yair Argon, PhD, could lay the foundations for future therapies. The study, which identified an enzyme the body uses to ameliorate endoplasmic reticulum stress, was published recently in Molecular Cell.

An organelle found in all eukaryotic cells, the endoplasmic recticulum (ER) plays an important role in the manufacture and delivery of enzymes, lipids, and proteins. When stress is placed on the ER — due to such things as environmental factors, hypoxia, and viral infections — cells’ ability to synthesize, fold, and mature proteins can be impaired.

This condition of ER stress has been associated with a wide range of diseases, including amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), bipolar disorder, cancer, diabetes, and heart disease.

Cells’ response to ER stress is the unfolded protein response (UPR), in which sensors are activated in an attempt to return the cell to homeostasis or, failing that, to induce apoptosis. In the Molecular Cell study, Dr. Argon and colleagues investigated the regulation of the UPR sensors.

Working with two postdoctoral fellows, Davide Eletto, PhD, and Daniela Eletto, PhD, as well as a graduate student, Devin Dersh, and in collaboration with Drexel University’s Tali Gidalevitz, PhD, the researchers found that the activity of one major sensor — inositol-requiring enzyme 1α (IRE1α) — is normally regulated by the enzyme protein disulfide isomerase A6 (PDIA6).

“We showed that this mechanism for limiting ER stress signaling and maintaining it within a physiologically appropriate range operates in cells in culture and also in an animal model,” Dr. Argon said. In PDIA6’s absence, several of the activities of IRE1α are exaggerated and PDIA6-deficient cells are more sensitive to ER stresses such as the presence of misfolded mutant insulin. Conversely, when there is excess activity of PDIA6, IRE1α activity terminates earlier, because PDIA6 modifies the activated sensor.

While the current study is basic, the research nonetheless “has important implications for many areas of physiology and multiple diseases,” Dr. Argon noted. “Because PDIA6 is an enzyme, one can imagine that its activity can be targeted by future development of small molecules, which may either inhibit it, when it is desirable to exacerbate the response and cause cell death, or activate it, when it is desirable to dampen the response.”

“Therefore, there are clear translational research avenues to be explored,” he added.

To read more about this study, see Molecular Cell.

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Gene Sequencing Test to Speed Donor Matching, Research


Immunogenetics experts at The Children’s Hospital of Philadelphia have developed a unique laboratory test to characterize the genes that encode HLA molecules. The test relies on faster, more comprehensive gene sequencing technology to type human leukocyte antigens (HLAs) — complex, highly variable proteins on cell surfaces that are essential to immune function.

The new test may improve transplantation outcomes through a more refined assessment of donor compatibility, and will expedite the donor selection process from bone marrow registries. It also provides an advanced tool for research in immunological diseases, infectious diseases, and pharmacogenomics.

“This new test addresses a sixty-year-old problem,” said Dimitri Monos, PhD, director of the Immunogenetics Laboratory in the Division of Genomic Diagnostics. “Since the discovery of HLAs in the early 1950s, it has been a challenge to accurately and thoroughly characterize HLA gene sequences. We have now used next-generation sequencing tools to significantly advance HLA typing.”

CHOP is the first hospital to offer this new comprehensive HLA-typing test. “This is a new, disruptive technology, with the potential to transform research and clinical practice, in transplantation and other fields,” said Robert Doms, MD, PhD, CHOP’s pathologist-in-chief.

HLA genes are the most complex gene family known in the entire human genome. Gene sequences for HLAs are extremely polymorphic — highly variable, to a degree not adequately captured by conventional typing tests. Current tests often provide ambiguous and limited results, by sequencing only segments of HLA genes and failing to distinguish among different alleles suggested by a given sequence. In addition, preliminary testing often must be followed by a second level of reflexive testing, adding expense and time to the HLA typing process.

The new test, says Dr. Monos, replaces preliminary and reflexive tests with a single test, providing the highest resolution possible by covering the full HLA genomic region. It can currently distinguish among 10,500 different alleles of all known HLA types and can fully characterize new alleles yet to be discovered. Next-generation sequencing is expected to dramatically increase the list of HLA alleles.

Dr. Monos and colleagues developed a new protocol for HLA genotyping using an Illumina sequencing platform, the MiSeq. The scientists validated the test by comparing its results against previously sequenced data from a collection of over 300 samples characterized at five different genes. The agreement between the two methodologies was 100 percent. CHOP will be offering the HLA typing test for patient testing as a service to medical and academic centers. The test is faster, more precise, and costs less than existing testing procedures.

The new test’s most significant short-range impact may be in typing donors in bone marrow/stem cell registries. Because of the high cost of performing high-resolution HLA typing under current methods, most potential donors are typed at low- or intermediate-resolution, with a repeat, high-resolution test needed to assess compatibility when a patient needs a transplant. The new method will save time and expense by initially typing donors at the allele level. Therefore, no additional typing will be necessary to assess compatibility.

“This faster, more thorough technology allows us to better account for subtle genetic differences between individuals,” said Dr. Monos. “We expect this knowledge to yield clinical benefits, by facilitating more precise matches between transplant donors and recipients, and assessing the significance of mismatches in genomic regions of the HLAs that were previously uncharacterized.

“Additionally, by focusing on fine details of immune responses, this technology can advance our understanding of how specific individuals respond to infectious diseases, to vaccinations, and to particular drugs. This test represents a potentially powerful tool in personalized medicine,” Dr. Monos added.

To learn more about Children’s Hospital’s genetic testing services, see the Division of Genomic Diagnostics. For more information about the HLA typing test, see the full press release.

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Campaign Raises Pediatric Palliative Care Awareness


Pediatric palliative care is a powerful intervention that can be prescribed alongside curative or life-prolonging therapies for children with serious illnesses. Research has shown that pediatric palliative care services can help reduce a child’s pain, help manage other distressing symptoms, and provide emotional support.

At Children’s Hospital, a nationally esteemed Pediatric Advanced Care Team (PACT) takes a comprehensive approach that focuses on psychological, social, and spiritual needs as a standard part of palliative care. Yet many families and caregivers elsewhere are not as familiar with palliative care’s benefits, and health care providers hesitate to recommend palliative care for their youngest patients.

Each year, more than 45,000 children die in the U.S., and three-quarters of these deaths occur in the hospital setting. The National Institute of Nursing Research (NINR) recently launched a national campaign, “Palliative Care: Conversations Matter,” to raise awareness of palliative care and increase its use within the pediatric population.

The NINR brought together parents, palliative care clinicians, and scientists to develop evidence-based materials designed to initiate dialogues about palliative care soon after diagnosis and throughout the course of an illness. CHOP’s Chris Feudtner, MD, PhD, MPH, director of research for PACT, was involved in planning the NINR campaign and has had several research studies funded by NINR grants, including an ongoing two-year cohort study focusing on decision-making in advanced pediatric care.

“Part of what the campaign addresses is concerns that parents may view the introduction of palliative care as an ominous sign that the medical team is stepping back,” Dr. Feudtner said.

“Palliative care is not exclusive to patients who are no longer seeking cure or no longer seeking life-prolonging therapy. It can be in addition to those type of therapies. The campaign can help physicians provide a more clear explanation of what palliative care is and allay fears.”

The “Palliative Care: Conversations Matter” campaign materials include informational video vignettes and tear-off pads of patient education sheets that guide providers in how to engage in interactive palliative care discussions. The NINR has received requests for these resources from across the U.S. and internationally.

“The response has been excellent so far,” according to NINR Director Patricia A. Grady, MD. “We’ve been pleased to see so many colleagues in palliative care and nursing organizations helping us spread the word.”

An important part of implementing the campaign is having skilled staff as ambassadors at the bedside to collaborate with parents and incorporate their perspectives into the palliative care plan, Dr. Feudtner said. CHOP’s PACT, for example, helps families understand their children’s underlying disease process and prognosis, optimize symptom control, establish a comforting environment, and promote their highest quality of life.

“You need to have high quality palliative care teams in place in order to make a bad situation as good as possible,” Dr. Feudtner said. A study he published in the December issue of Pediatrics showed an explosion in the number of palliative care teams over the past 10 years in the U.S. Of 162 children’s hospitals that provided data for the study, 69 percent reported having a pediatric palliative care program.

“NINR’s campaign will help raise awareness of and demand for pediatric palliative care among health care providers and patients, which we hope will encourage the continued growth in research in this important field,” Dr. Grady said.

Dr. Feudtner’s current research aims to improve understanding of how parents make extremely difficult medical decisions for children with life-threatening complex chronic conditions. The findings of his previous studies have emphasized the importance of psychology and the emotional realities involved in this daunting challenge.

Building on research papers published in 2010 and 2012 describing decision-making by parents of children receiving palliative care consultative services, the current CHOP cohort study is following 200 parents and 163 children. Dr. Feudtner and colleagues are examining the process of decision-making longitudinally and the impact on decision-making of hopeful patterns of thought, positive and negative affect, and the child’s illness trajectory.

“Our team and our experience at CHOP have helped us to heed the potential of what palliative care can do from many different angles,” Dr. Feudtner said. “And our research is taking us further. We have bedside learning from clinical practice intermixing with and informing health services and epidemiological research.”

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CHOP Research Honors Distinguished Trainees

Distinguished Trainees

During The Children’s Hospital of Philadelphia Research Institute’s recent Poster Day event, the 2014 Distinguished Research Trainee Award winners were announced. Comprised of a physicist, a molecular biologist, and a cancer geneticist, this year’s awardees’ expertise spans the research spectrum.

University of Pennsylvania doctoral candidate Jennifer Lynch, as well as James Psathas, PhD, and Jennifer Kalish, MD, PhD, a postdoctoral fellow and a physician fellow, respectively, were recognized with this year’s Distinguished Trainee Awards.

The CHOP Distinguished Research Trainee Awards provide institution-wide recognition for exceptional CHOP Research trainees, and create an avenue for mentors to show appreciation for their researchers-in-training. Each awardee is featured on the CHOP Research Office of Postdoctoral Affairs (OPA) Trainee Web Portal, recognized with an award certificate, and awarded a cash prize.

Selected from among 14 nominations, this year’s winners were chosen by members of the Research Trainee Advisory Committee, which is chaired by the Center for Injury Research and Prevention’s Dennis Durbin, MD, MSCE. The winners were presented with certificates of achievement by Philip Johnson, MD, CHOP Research’s chief scientific officer.

 A Physicist, a Biochemist, and a Geneticist

After receiving her bachelor’s degree from Emory University, Jennifer Lynch came to the University of Pennsylvania to pursue a doctorate in physics, with a concentration on biomedical optics. Since 2010 she has worked with Daniel J. Licht, MD, of Children’s Hospital’s Department of Neurology, aiding in several congenital heart defect investigations as well as using optical spectroscopies to monitor cerebral hemodynamics.

Lynch was the winner of the “Outstanding Investigator” Award at Cardiac Center’s Cardiology 2014 conference in Orlando, Fla., in February. She has also been the lead author on a number of recent papers, including a recent Academic Radiology study on using near-infrared spectroscopy to measure cerebral venous oxygen saturation, while another paper was recently submitted to the Journal of Thoracic and Cardiovascular Surgery.

“Most physics graduate students would shy away from clinical studies,” but Lynch “wholeheartedly embraces” and relishes in the complexity of clinical physiology, Dr. Licht said, adding, “I see a very bright future for her at the interface of physics and clinical research.”

“What I’ve enjoyed most is working with patients and their families,” said Lynch, who will be attending medical school at New York University in the fall. “This chance to experience and contribute to medical research has really opened my eyes to how interesting this field is and how exciting it is to be part of the research,” she added.

The second awardee, James Psathas, PhD, was nominated by Andrei Thomas-Tikhonenko, PhD. A molecular biologist and biochemist, Dr. Psathas studies the mechanisms of oncogenesis. In 2012 he contributed to a Journal of Clinical Investigation study of CD19, while in December 2013 Dr. Psathas was the first author of a Blood paper on B cell signaling. In both cases, it was Dr. Psathas’ “painstaking bioinformatics work” that led to successful publication, Dr. Thomas-Tikhonenko pointed out.

“In addition to performing a tremendous amount of high-quality bench work and scholarly writing,” and becoming the “de facto bioinformatics guru of my lab,” Dr. Psathas has “two major strengths: tenacity and outstanding work ethics,” Dr. Thomas-Tikhonenko said.

“I have to thank CHOP as a whole, and especially Dr. Thomas-Tikhonenko for the commitment to and support of my research,” Dr. Psathas said. “It is gratifying to have one’s hard work recognized and I hope this award brings further awareness to the multitude of exciting research endeavors at CHOP.”

And rounding out the 2014 Distinguished Research Trainee award winners is geneticist Jennifer Kalish, MD, PhD, who was nominated by Matthew Deardorff, MD, PhD. Dr. Kalish, who is currently working in the laboratory of the University of Pennsylvania’s Marisa S. Bartolomei, PhD, is also an attending physician in the Division of Genetics as well as an instructor in Pediatrics at the University of Pennsylvania.

Much of her work has been focused on better understanding Beckwith-Wiedemann Syndrome (BWS), a rare genetic overgrowth disorder that is associated with an increased risk of childhood cancers, in particular kidney cancer and hepatoblastoma, a form of liver cancer. In late 2013 Dr. Kalish received a “Young Investigator” grant from Alex’s Lemonade Stand Foundation to further study the mechanisms of BWS.

“There’s such amazing research that goes on at CHOP, and it’s an honor to be recognized as part of that research,” Dr. Kalish said.

Saying he was “very enthusiastic” about her research, Dr. Deardorff noted that Dr. Kalish “is enthusiastic, hardworking, proactive, and dedicated to her patients and pursuit of better treatments. She is passionate about science and is focused on the translation of basic research mechanisms into the clinic.”

To read more about each of this year’s awardees, and to learn more about training opportunities at CHOP Research, see the Office of Postdoctoral Affairs Trainee Web Portal.

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Pediatric Psychology Experts Set to Shine at SPPAC


Pediatric psychology is a key component of family-centered care at The Children’s Hospital of Philadelphia. When a child has a serious or chronic illness, pediatric psychologists listen carefully and empathetically to concerns of the young patient and family while assessing their strengths, coping strategies, and goals. Pediatric psychologists also work to improve the welfare of well children in healthcare settings, and they conduct a variety of research activities, such as finding ways to increase adherence to medical treatments.

Several of CHOP’s experts in this multidisciplinary field will be sharing their insights at the Society of Pediatric Psychology Annual Conference (SPPAC), set to be held in Philadelphia March 27-29. The three-day conference will take place at the Loews Hotel in Center City Philadelphia, and it is expected to draw more than 500 researchers and practitioners from the Delaware Valley and beyond.

The SPPAC will introduce a fresh format for the meeting, which will attract pediatric psychologists, researchers, and other specialists who have training and experience in addressing the emotional, cognitive, and developmental needs of medically fragile children. SPPAC Chairperson Lisa Schwartz, PhD, a psychologist in CHOP’s division of oncology, has organized many of the new elements that will be integrated into the 2014 conference.

“It’s been exciting to help shape the conference and be a firsthand witness to all the innovation in the field,” said Dr. Schwartz, who will officially welcome SPPAC attendees during opening remarks March 28.

A “first” for the conference is the incorporation of a theme, “Pediatric Psychology: From Infancy to Adulthood.” Presentations will reflect a lifespan and developmental perspective that focuses on findings from early childhood to young adulthood. They also will promote the maturation of the science of pediatric psychology via technology, advanced statistical or research designs, translational science, and team science. And the conference will offer more workshops and concurrent symposia than ever before along with research blitz sessions that will cover novel and noteworthy advances, Dr. Schwartz said. Fifteen special interest group meetings will facilitate collaboration.

Captain Steven Hirschfeld, MD, PhD, director of the National Children’s Health Study, will present the keynote presentation, “An Integrated Framework for Linking Exposure and Phenotypic Data in the National Children’s Study.” By following 100,000 children from before birth to age 21, study researchers hope to better understand how children’s genes and their environments interact to affect their health and development. The Children’s Hospital of Philadelphia is a site of this important study.

CHOP psychologists will also present talks throughout the conference, including one that Dr. Schwartz will give March 28 on young adults’ transition to adult medical care. Dr. Schwartz highlighted a few other “not-to-miss” examples of CHOP’s contribution:

SPPAC provides an ideal forum for networking and career building. Students, trainees, and early career professionals who pre-register for a mentoring lunch March 28 will have the opportunity to consult with more than 25 established investigators and clinicians from CHOP who can help them to navigate research careers in pediatric psychology.

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Congratulations to the 2014 Poster Day Award Winners!


The Children’s Hospital of Philadelphia Research Institute celebrated its 24th CHOP Research Poster Day on February 26, 2014, with more than 160 cutting-edge research posters on display in the Colket Translational Research Building. This annual event recognizes the outstanding research conducted at CHOP each year and honors our exceptional trainee participants.

This year 40 individuals were selected by our faculty judges to receive awards for their outstanding Poster Day presentations in the patient-oriented research and laboratory-based tracks. Winners can be viewed on the CHOP Research intranet.

We also raffled off three prizes to our event attendees. The winners of the prizes include:

For more information about CHOP Research Poster Day and to review abstracts submitted for the event, please visit the Research Poster Day web site.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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