Bench to Bedside

May 2015

It’s Not a Just Job, It’s an Adventure: The 2015 Research Symposium


Bookended by references to the 1980s and 1990s — in the form of an iconic U.S. Navy commercial and a discussion of the 1991 measles outbreak in Philadelphia — the 2015 CHOP Research Institute Scientific Symposium offered a snapshot of the inspirational work going on at Children’s Hospital every day. Researchers from a variety of disciplines gave talks on everything from the challenges intrinsic to running a large research enterprise, to the human microbiome, to traumatic brain injury.

The day started off with a presentation from Dennis Durbin, MD, MSCE, director of CHOP Research’s Office of Clinical and Translational Research (OCTR). Dr. Durbin, who took OCTR’s reins after many years at the Center for Injury Research and Prevention, is a recognized leader in pediatric injury prevention research. Discussing his time at the helm of OCTR, Dr. Durbin compared the work of aiding investigations to the aforementioned Navy commercial, the tagline of which is “Navy. It’s not just a job, it’s an adventure”.

The morning’s first session saw two more presentations, from gene therapy expert Beverly Davidson, PhD, and rheumatologist Edward M. Behrens, MD, on gene therapy and hemophagocytic syndromes, respectively.

Dr. Davidson’s talk, which she gave alongside Alex Max Monteys, PhD, a senior research scientist her lab, was largely focused on the neurodegenerative disorder Huntington’s disease. Characterized by uncontrolled movements and progressively worsening mood issues and cognitive abilities, the condition affects approximately 10 to 17 per 100,000 live births. Dr. Davidson and her team have been investigating using RNA interference to mitigate Huntington’s disease in animal models.

Dr. Davidson’s talk set the tone for much of the rest of the day, as many symposium presentations were highly focused, often basic, microbiological, immunological, and genetic investigations. An exception was the presentation by Yi-Ching Lee, PhD, on her work developing computational techniques to model teen drivers’ behaviors. A human factors researcher at the Center for Injury Research and Prevention, Dr. Lee has been working on a driving simulator that can learn from its users to model teen drivers’ behavior.

Let’s Do Lunch

The timing of the symposium’s external keynote speech — by Ronald M. Evans, PhD, of the Salk Institute —was particularly appropriate this year. As attendees ate lunch, Dr. Evans gave a talk on nuclear receptors, a class of proteins that play a key role in metabolism.

A faculty member at the Salk Institute since 1978, Dr. Evans has also been a Howard Hughes Medical Institute investigator since 1985. His numerous awards and honors include a 2004 Albert Lasker Basic Medical Research Award and the 2012 Wolf Prize in Medicine. He is an internationally recognized, leading researcher in nuclear receptors and the mechanics of metabolism.

During his speech, Dr. Evans discussed the research that led to the development of fexaramine, an investigational compound developed in his laboratory that, per the Salk Institute, “tricks the body into thinking it has consumed calories, causing it to burn fat.” In February Dr. Evans and colleagues published a study in Nature Medicine showing fexaramine activates the bile-activated farnesoid X receptor, stimulating the metabolism-related mouse protein fibroblast growth factor 15.

In short, fexaramine, “reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production,” which “pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome,” the authors wrote.

After lunch — with empty heads and full stomachs, to borrow from Dr. Evans’ talk — symposium attendees settled in for a series of talks about vaccinology, genetics, neurology, and oncology. A highlight was the presentation given by former Chief Scientific Officer Philip R. Johnson, MD, on his lab’s work developing an HIV vaccine.

Dr. Johnson has been on the leading edge of HIV vaccine research for years. In 2009 he published a study in Nature Medicine in which he worked with simian immunodeficiency virus (SIV) — the simian cousin of HIV — to develop proteins that act like antibodies called immunoadhesins. These proteins, delivered intramuscularly through adeno-associated virus vectors, were designed to prevent SIV from infecting cells. The researchers found the immunoadhesins blocked SIV infection, protecting the primates used in the study.

Dr. Johnson’s work has led to a Phase 1 clinical trial sponsored by the International AIDS Vaccine Initiative to study the safety of the vector carrying the broadly neutralizing antibody PG9, which has been shown to protect against HIV.

“In essence, it’s like a Trojan horse,” Dr. Johnson said. “This coding is carrying the gene of interest. That virus then can infect the muscle cell. It deposits the gene into the cell. … There it sits and makes antibodies that extravasate into the circulation.”

And last, but most certainly not least, the day’s events were capped off by a presentation by Paul A. Offit, MD. Perhaps CHOP’s best-known and most outspoken vaccine advocate, Dr. Offit is co-creator of the rotavirus vaccine Rotateq, director of the Vaccine Education Center, and author of numerous books, the latest of which is Bad Faith: When Religious Belief Undermines Modern Medicine.

Dr. Offit discussed the 1991 Philadelphia measles outbreak in depth, with a focus on the role several churches played in the outbreak. Though it was largely dormant in the U.S. for many years, measles seems to be somewhat resurgent, with 166 cases diagnosed between January 1 and April 24, 2015, in the District of Columbia and 17 states across the U.S., according to the CDC. The recent rise in measles cases is largely due to children and adults not being vaccinated.

“The reason that we’re hearing about these epidemics is because parents aren’t vaccinating their children because they’re not scared of the disease,” Dr. Offit said. “But I am.”

To learn more about the day, and to see the entire 2015 CHOP Research Institute Symposium’s lineup of presentations, check out the Symposium web page.

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Despite Care Improvements, Cardiac Surgery Affects Infants’ Neurodevelopment


Cardiac specialists have worked for many years to help high-risk infants with complex congenital heart disease (CHD) survive surgery. As advances in surgical and perioperative care have improved their success rates dramatically, researchers, clinicians, and families are now able to turn their attention to these children’s long-term outcomes.

The most common complication for children who undergo CHD surgery in infancy is neurodevelopmental disability. Previous research has shown that they have lower abilities with reasoning, learning, executive function, inattention and impulsive behavior, language skills, and social skills compared to the general pediatric population.

The International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators looked at trends over a 14-year interval in neurodevelopmental outcomes for survivors of CHD surgery. Twenty-six institutions from six countries — the U.S., Canada, Austria, New Zealand, Japan, and Switzerland — submitted study participant data for the pooled analysis project. The study team evaluated 1,770 children born between 1996 and 2009 who underwent CHD surgery, which is the largest cohort reported to date.

The investigators assessed the study participants’ scores at age 14.5 months on the Bayley Scales Version 2, a standard series of measurements that examine multiple facets of child development. They reported that these scores were significantly lower than expected compared with the general population.

“We showed that over the last 15 years, despite all the improvements in care, we have really made very little progress in improving the long-term neurodevelopmental outcomes for these kids,” said J. William Gaynor, MD, first author of a Pediatrics article that reported the ICCON investigators’ results.

“Once you’re past the excitement and stress of the operation, this is what parents really care about: Is my child going to need special education? Is my child going to have attention-deficit/hyperactivity disorder? Is she going to be able to have a job? Is he going to be able to have a family? That’s what we’re trying to answer,” Dr. Gaynor said.

The ICCON investigators will continue their worldwide collaboration to study factors that may explain the lack of greater improvement in early neurodevelopmental outcomes over the study period. The study team already is gathering data to determine if there is any relationship between intraoperative management strategies and neurodevelopmental outcomes. Another possibility is that brain development in children with CHD is immature prior to birth.

“The data here is suggestive that if you’re going to make these kids better, we’ve got to make their brains better before they’re even born,” said Dr. Gaynor, who is an attending cardiothoracic surgeon at The Children’s Hospital of Philadelphia and associate professor of surgery at the University of Pennsylvania School of Medicine.

“Our goal is that when you meet these kids, if you didn’t see the scar on their chests, you would not know that they had heart surgery because they’re completely like every other kid in every other way,” added Dr. Gaynor. “We’re not there yet, but this is the type of research that we need to get us there.”

The pooled data analysis project was funded by a grant from the Mend-a-Heart Foundation.

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Filling Prescriptions After Hospitalization Reduces Asthma Readmissions


Imagine the following scenario: you or your child are hospitalized, and upon discharge are given a prescription by your doctor to treat the underlying condition. And, hopefully, to prevent you or your child from having to be hospitalized again. Simple enough, right? One would think, in such a scenario, patients would fill their prescriptions ten out of ten times.

Unfortunately, patients and their families don’t always fill their prescriptions, even if not doing so means they could end up in the hospital again. New asthma-related work published in The Journal of Pediatrics shows just over 50 percent of a large cohort of pediatric patients filled beta agonist and oral steroid prescriptions after being hospitalized for asthma, and fewer than 40 percent filled inhaled steroid prescriptions.

The study was led by The Children’s Hospital of Philadelphia’s Chén Kenyon, MD, MSHP and Chris Feudtner, MD, PhD, MPH. Dr. Kenyon is a PolicyLab faculty member and an attending physician in the Division of General Pediatrics. In addition to his role as Director of Research for Children’s Hospital’s Pediatric Advanced Care Team, Dr. Feudtner is also director of the Department of Medical Ethics at CHOP.

One of the most common diseases of childhood, asthma is one of the leading reasons children seek medical attention. According to 2013 CDC data, 8.3 percent of U.S. children under the age of 18 have asthma, and in 2011 there were 1.8 million emergency department visits for asthma-related causes. Likewise, in 2010 there were 14.2 million primary care physician visits related to asthma, per the CDC site.

“Asthma is a leading cause of childhood hospitalization and the most common cause of preventable hospitalization,” the investigators note in the Journal of Pediatrics study. The study fits into one of PolicyLab’s broad areas of investigation, improving health care delivery.

The NIH’s National Asthma Education and Prevention Program guidelines recommend patients who have been hospitalized for asthma be given several medications, “including continuation of inhaled short-acting beta agonists and oral steroids, along with continuation or consideration of initiation of a preventative controller medication such as an inhaled corticosteroid,” the study’s authors note.

However, as they note, adherence to these guidelines has not been evaluated broadly, and prescribing and fill rates vary. So with this study the investigators sought to determine the percentage of patients who actually filled prescriptions following hospitalization, and what effect filling prescriptions had on readmission rates.

Using Medicaid data, Drs. Kenyon and Feudtner identified a total of 31,658 children aged 2 to 18 across the U.S. who were admitted for asthma between January 1, 2006 and September 3, 2007. The researchers found roughly 55 percent of children filled beta agonist or oral steroid prescriptions within three days of discharge, while 37 percent filled prescriptions for inhaled steroids. After including inhaler fills that occurred in the month prior to hospitalization, rates for beta agonist fills increased to 67 and 45 percent for inhaled steroids.

With fill rates in hand, the researchers then turned to readmission rates. They found patients who filled beta agonist and inhaled steroid prescriptions had lower readmission rates within 14 days of discharge. Oral steroids were also associated with a drop in readmission rates, but the change was not statistically significant.

“Those who filled prescriptions for short-acting beta agonists and inhaled steroids experienced early readmission less frequently than children who did not, and those who filled inhaled corticosteroids experienced 15- to 90-day readmission less frequently than those who did not,” the authors note.

“These findings suggest that children hospitalized for asthma should be prescribed and fill recommended discharge medications,” the authors conclude.

“These results may not surprise many, but few practices have been shown to reduce hospital readmissions,” said Dr. Kenyon. “Though this is a retrospective study that cannot confirm causality, these findings offer a compelling connection between something relatively straightforward that we can do at the time of discharge (make sure patients have their medications in hand) and better outcomes. In the era of accountable care, all healthcare stakeholders stand to benefit from such a practice.”

To learn more about asthma care and research at The Children’s Hospital of Philadelphia, see the Asthma Program and PolicyLab’s website.

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Precision Medicine Trial to Focus on Children With Advanced Cancers


When a clear, curative pathway is not available for pediatric cancers that relapse, families often will turn to new, experimental treatments being studied by The Children’s Oncology Group with hopes of exploring other options to care for their children. A new research opportunity under development as part of its Project:EveryChild, called Project:EveryChild Pediatric MATCH (Molecular Analysis for Therapy Choice), aims to use the power of precision medicine to potentially provide investigational therapies for some children with advanced cancers.

The Children’s Oncology Group, a collaboration of more than 220 leading children’s hospitals, universities, and cancer centers from across the globe — including The Children’s Hospital of Philadelphia — is the world’s largest organization devoted exclusively to childhood and adolescent cancer research.

Each year, nearly 13,500 children and teens are diagnosed with numerous types of cancer. Within those types of cancer, there are multiple subsets of disease. Some are harder to treat than others. Scientists suspect that the tumors involved in those stubborn cases may have different genetic alterations that help them to resist standard therapy and begin to grow.

“Pediatric MATCH will try to match genomic changes in certain children’s cancers with drugs that are either approved for adult cancers or with drugs that are still under investigation and not yet approved,” said Peter Adamson, MD, chair of the Children’s Oncology Group and a pediatric oncologist at CHOP. “The other goal is to try to understand if there is a genomic basis for when our treatments fail and how the cancers may have changed from the time of original diagnosis.”

While Pediatric MATCH is still under development, Dr. Adamson expects that the study enrollment will include about 300 children each year with advanced cancers that have progressed on standard therapy. Although only some of these children will have cancers that can be matched to a new drug, a significant aspect of Pediatric MATCH is those children with matches will be assigned to a phase II research protocol based on the genetic abnormality that seems to be fueling their disease progression, not the type of cancer.

After the child undergoes a tumor biopsy at relapse, some of the tissue will be sent to a centralized center for specific tests that may include next-generation DNA sequencing. Once investigators identify the tumor’s genomic changes and characteristics, they will sort through a group of 20 to 25 selected targeted drugs to see if one has shown some efficacy against tumors with the same genetic alterations. Should a match be found, the child will then be able to receive that drug to see if it is of some potential benefit.

“What we know to date about the genomics of cancer at diagnosis and at relapse is that perhaps there are somewhere in the order of about 15 percent of cancers that may have a finding for which we may have a drug,” Dr. Adamson noted.

In a unique arrangement, the Pediatric MATCH trial is a combined effort of the Children’s Oncology Group, the National Cancer Institute (NCI), and a range of pharmaceutical companies that already have committed to providing drugs to be tested in an adult NCI MATCH Trial slated to begin this year. Dr. Adamson anticipates that many of this similar counterpart trial’s pharmaceutical agreements will carry over to Pediatric MATCH. New drugs could be added to the trials over time.

“That is of great importance to this project because all childhood cancers are rare diseases, and there generally isn’t an economic model for pharmaceutical companies to study childhood cancers,” said Dr. Adamson.

While the Children’s Oncology Group has partnered successfully in the past with companies to provide two different experimental drugs in a single research trial, Pediatric MATCH will be a significant leap beyond that model. Dr. Adamson estimates up to 10 companies will be participating in Pediatric MATCH, and each will receive information that will advance knowledge, may benefit children, and also could help the companies to accelerate their drug development.

“We hope that we will be able to see signals of efficacy that these drugs are working that would then lead to potentially additional trials that become disease-specific for that drug,” said Dr. Adamson. “Well-defined genomic testing may one day provide a lead to having a portfolio of drugs that may be of benefit to the child.”

The Pediatric MATCH study team also will share tumor analysis results with the child’s cancer specialists to help them guide the family’s treatment choices. In addition, the tissue samples will be highly valuable to future researchers as they try to explain the basis of cancer treatment failure and relapse.

“If we find that a certain pathway is very important for a disease or subset of diseases, we can build upon that and perhaps bring new treatments into that disease area, not only for relapsed cancer, but potentially to move those treatments earlier into therapy for appropriate populations,” said Dr. Adamson, who also is a professor of pediatrics and pharmacology at the Perelman School of Medicine at the University of Pennsylvania.

Pediatric MATCH is a high priority for the Children’s Oncology Group, Dr. Adamson said, with five working groups focused on an aggressive timeline of launching the trial toward the beginning of 2016.

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Cookies for Kids’ Cancer Funds Support Discovery of New Therapies


What comes in a “Box of Hope?” Inside you will find three kinds of scrumptious cookies, but what you are truly unwrapping is the potential for pediatric cancer researchers to advance novel treatments to clinical trial as quickly as possible.

Cookies for Kids’ Cancer, a nonprofit foundation dedicated to pediatric cancer research, uses the proceeds from its cookie sales and other fundraising events to provide grants to support the work of scientists at five of the nation’s leading pediatric cancer centers. The Children’s Hospital of Philadelphia has received continuous funding since the Cookies for Kids’ Cancer foundation was established in 2008. Most recently, two CHOP teams received a total of $200,000 in grants to focus on pediatric neuroblastoma and acute myeloid leukemia (AML) research.

John Maris, MD, a CHOP pediatric oncologist and the Giulio D’Angio Chair in Neuroblastoma Research, met the Cookies for Kids’ Cancer founders, Gretchen and Larry Witt, when their son, Liam, was at CHOP to receive treatment for neuroblastoma. An aggressive cancer of the peripheral nervous system that usually appears as a solid tumor in the chest or abdomen, neuroblastoma accounts for 7 percent of all childhood cancers, but it causes 15 percent of all childhood cancer deaths.

“The family saw early on that for children who have relapsed or refractory types of cancers there was a huge gap in funding,” said Dr. Maris. “There were not enough effective treatments, and the key to changing that was research.”

In the first Cookies for Kids’ Cancer bake sale, Gretchen baked and sold 96,000 cookies with the help of 250 volunteers, raising more than $400,000 for research. Since 2008, the foundation has supported four dozen childhood cancer research grants that have led to nine new treatments being tested in clinical trials.

“The foundation is unique in that it will only fund research projects where there is a tangible deliverable to the clinic,” said Dr. Maris, who also serves on the foundation’s medical advisory board and gives advice on other institutions’ projects that have the highest potential to make an impact.

That is certainly the case for Dr. Maris’ research program, which is capitalizing on findings supported by a previous Cookies for Kids’ Cancer grant that helped investigators to identify a good therapeutic target called CDK6, which is a protein that is hyperactivated in certain neuroblastoma tumors. The current grant will extend this discovery.

Some cancer cells can figure out how to escape a single drug target. Lori Hart, PhD, a senior research scientist, is leading a program within Dr. Maris’ study team and focusing on a combination approach that aims to promote the killing of neuroblastoma cells with two new drugs in development. One inhibits CDK6, while the second inhibits MEK, a molecule that is part of a signaling pathway essential to regulating many cellular processes. Dr. Hart has shown therapeutic synergy when these two drugs are used together in neuroblastoma models.

“Cells that may be a little bit sensitive to one drug or a little bit sensitive to the other drug appear to be very, very sensitive to both,” said Dr. Maris. “There is exquisite cell death in our laboratory models.”

Based on these results, Dr. Maris has proposed a clinical trial to see if the novel combination therapy shows any benefit for children with neuroblastoma whose tumors have the genetic vulnerabilities that these drugs target. He expects that about 30 percent of children with relapsed neuroblastoma will fit the genetic qualifications required to enter the trial.

Chimeric Antigen Receptor Immunotherapy for Pediatric AML

Cookies for Kids’ Cancer is also supporting drug discovery research for AML, another pediatric cancer that urgently needs new drug options to prevent relapses and improve long-term cures. AML is the second most common blood cancer in children, affecting about 500 children in the U.S. each year. Despite treatment with the most intensive multi-agent chemotherapies available, approximately 30 to 40 percent of children with AML will relapse.

“We’re just so thankful for the support from Cookies for Kids’ Cancer,” said Richard Aplenc, MD, PhD, a CHOP pediatric oncologist and Hematologic Malignancies section chief. Dr. Aplenc and his co-investigator Sarah Tasian, MD, also a CHOP pediatric oncologist and physician-scientist, are leading the study that aims to increase therapeutic strategies for AML by rigorously testing new chimeric antigen receptor T cell (CART) approaches. “This funding will make a world of difference in our research.”

A team of investigators at CHOP and the University of Pennsylvania leads the CART field in pediatric leukemias and has demonstrated remarkable success using immunotherapy for acute lymphoblastic leukemia (ALL). B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous.

The study team demonstrated in a groundbreaking trial that they could genetically program immune system T cells taken from patients’ own blood. The bioengineered “hunter” T cells, called CTL019, multiplied when they were returned to the patients’ bodies and eliminated the malignant B cells. One of the first pediatric patients to receive the investigational treatment — formerly known as CART19 — achieved a complete response and remains cancer-free now three years later.

Progress in using CART for AML, however, has proven to be more problematic so far. Many of the protein targets that researchers have identified on AML cells also appear at lower levels in normal cells that are critical to bone marrow formation. In previous studies, Dr. Tasian and colleagues have shown that CART cells can be successfully engineered to attack the protein CD123 on AML cells in mouse models, but this toxicity is long-lasting and has side effects on healthy bystander cells.

In the Cookies for Kids’ Cancer study, Drs. Aplenc and Tasian will investigate various “suicide switch” modifications to CART123 technologies that will allow effective eradication of AML but then turn off the CART cells to minimize collateral damage to healthy tissues.

“We’re looking at ways either to eliminate the T cells after they’ve killed the leukemia, perhaps with a treatment with an antibody, or even incorporation of a gene into the T cell itself that we can then turn off with a chemical or medication,” said Dr. Tasian.

In addition to finding an effective CART123 termination approach, the AML team is studying other proteins expressed by AML cells with the goal of identifying potential candidates for new CAR-based immunotherapies. Their ability to gain a better understanding of leukemia biology and explore more CAR strategies is crucial, as it is unlikely that a single agent will achieve a cure for the broad spectrum of children with AML.

Drs. Aplenc and Tasian, who are also associate and assistant professors of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, respectively, ultimately hope to develop a spectrum of innovative immunotherapies that will translate swiftly to the clinic. Based upon the team’s initial preclinical findings, a phase 1 trial of immunotherapy for pediatric AML is already under development in conjunction with co-investigators at the University of Pennsylvania.

“There is a very big need for new therapies in AML because there is not a pipeline of medications that are coming through and are available for children,” said Dr. Aplenc. “This grant is fantastic for us because its resources helped us to get started rapidly on an exciting new project.”

Sounds like both study teams are going to work up an appetite over the course of the two-year grants. Cookies, anyone?

For more information visit the Cookies for Kids Cancer website.

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Children With Nightly Bedtime Routines Have Better Sleep Outcomes


Sweet dreams. G’nite. Shubh ratri. No matter how you say it, a consistent bedtime routine makes a difference in children’s sleep outcomes, according to a study that included mothers of 10,000 young children from 14 countries.

Sleep problems in children are a common concern among parents, and increasing evidence suggests that inadequate sleep can lead to behavioral and cognitive consequences. Most parenting books and pediatricians recommend a bedtime routine as an effective way to improve children’s sleep difficulties, but this research is the first to demonstrate its importance in a dose-dependent way.

“With each additional night that a family institutes a bedtime routine, their child’s sleep is better,” said Jodi A. Mindell, PhD, associate director of the Sleep Center at The Children’s Hospital of Philadelphia, who reported the results in the journal Sleep. “It was a universal finding. We found it across a multitude of countries, which is amazing.”

Dr. Mindell and her co-investigators collected the data online from a questionnaire offered on a popular parenting website and through emails. The questions asked mothers of children ages 0 to 5 about their child’s daytime and nighttime sleep patterns and behaviors.

Overall, the results suggest that a regular nightly bedtime routine is associated with earlier bedtimes, shorter time needed to fall asleep, fewer awakenings after sleep onset, more total sleep, decreased parent-perceived sleep problems, and decreased daytime behavior problems. They also found that children who start sleep routines as infants are likely to have better sleep outcomes as they grow into toddlers and preschoolers.

“This is a clear message that for every family a bedtime routine should be recommended,” Dr. Mindell said. “A pediatric practitioner should ask how many nights a week they do it, and then encourage them to try to increase it, even it’s just by one night.”

In future studies, the researchers would like to take a closer look at which activities before lights out are most effective at improving children’s sleep. For example, does a relaxing bath before bed or reading a book result in better outcomes? Or, on the other hand, does an energetic 2-year-old benefit from more lively engagement before being tucked in?

“Sometimes I think it is frustrating for families because they have a hard time making bedtime calm for a child who has a lot of energy and won’t sit still for books,” said Dr. Mindell. “Maybe it’s OK to have a more active aspect of your bedtime routine, as long as it’s done every night and it’s an effective signal to your child. We don’t know yet.”

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Pathways in Cornelia de Lange Syndrome Open New Possibilities


Cornelia de Lange Syndrome (CdLS) is a relatively rare developmental diagnosis that involves a constellation of symptoms affecting almost every body system in children who have the most severe form of the diagnosis. Finding out its causes could be extremely important to understanding human development at all levels, which is why Ian Krantz, MD, medical director of the Center for Cornelia de Lange Syndrome and Related Diagnosis at The Children’s Hospital of Philadelphia, and his colleagues have dedicated the past two decades to research that is piecing together the basic biology of CdLS.

A unique aspect of the studies, which have been funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is that they are collaborations among scientists from across the country who started out by studying yeast and then small flies called Drosophilia, continued on to analyze zebrafish and mouse models, and then translated their findings to humans.

“This is a model of how you can go from a rare diagnosis, studying it clinically, and providing excellent care to the kids and the families, and then leveraging that population for discovery to find the genes and causes, and then to move on to the next level, which would be therapeutics, and hopefully give that back to the families,” said Dr. Krantz.

In recognition of the recent Cornelia de Lange Syndrome Awareness Day, here is a look at the projects’ history and recent findings.

Finding the First Genetic Mutation That Causes CdLS

Most children with CdLS do not inherit the disease from their families. It results from a new change in their genetic makeup, which can be tricky to find. Using DNA sequencing technology, Dr. Krantz’s study team made an exciting discovery in 2004 when they identified the first gene, NIPBL, which causes CdLS when altered or mutated.

The gene, and the pathway it controls — called cohesin — had never been known to be mutated in any other human condition, but it is essential to cell division. Humans have 23 pairs of chromosomes that are packages of DNA, a long molecule that contains our unique genetic information. When new cells are forming, two daughter cells separate at a precise moment toward the very end of cell division and are released with duplicate copies of each chromosome.

The process that holds these duplicated chromosomes together until the end of cell division is known as sister chromatid cohesion and is regulated by cohesin, a protein complex. If it is disrupted, the chromosomes cannot go into the new cells in the right number or complement, and that is generally lethal to the cells.

Creating a ‘New Realm of Biology’

Dr. Krantz’s co-investigator, Dale Dorsett, PhD, of the department of Biochemistry and Molecular Biology at St. Louis University School of Medicine, revealed in his studies of Drosophilia that NIPBL and cohesin play another integral role in gene expression, a complicated process that involves elements in DNA called regulators that act as enhancers and repressors for target genes. Basically, these regulators communicate with a region of a gene called a promotor that tells the gene when to turn on or off, what cells to turn on or off in, and how much the gene should be turned on or off.

About 60 percent of the children with CdLS have an NIPBL mutation that the study team suggests interferes with cohesin’s role in the regulation of normal gene expression, resulting in diverse genes being turned on or off at inappropriate levels in different cells during development. For example, a child’s heart cells or brain cells may not form properly because the appropriate genes are not being told to turn on at certain levels at the right time. Since sister chromatid cohesion defects are not seen in CdLS, the investigators suggest that early dysregulation of appropriate gene expression during development is what causes the symptoms seen in children with CdLS, which include limb differences, developmental delays, autistic-like behaviors, small stature, cardiac problems, and gastrointestinal issues.

“So this is a whole new realm of biology that has been created, which is cohesin’s role in gene expression regulation and development,” said Dr. Krantz. “It has many, many roles, and it’s been one of the complexes now that is at the core of all cellular processes. It’s become a very important, very basic, fundamental biologic pathway.”

Advancing Understanding of Isolated Birth Defects

In order to further understand the basic molecular determinants of structural birth defects, the next step was to build a biological model using zebrafish and mice. Developmental biologists at the University of California Irvine, Arthur Lander, MD, PhD, and his wife, Anne Calof, PhD, had a child with CdLS who died as a newborn. They wanted to help the researchers understand how the NIPBL gene functioned. They joined Dr. Krantz and Dr. Dorsett in successfully submitting the initial grant application to the NICHD in 2006 to leverage this information to find causes for the isolated birth defects that are seen in constellation in CdLS.

Since then, the team has achieved many discoveries, including identifying four more genes that cause CdLS when mutated all involved in the cohesin pathway. The NICHD grant was renewed in 2011, which is allowing the study team to figure out if cohesin is a master switch that regulates many genes’ expression. So far, they have found about 240 genes out of 20,000 in the human genome that are significantly up or down regulated consistently among children with CdLS. The next step is to determine if any fluctuations in those genes could disrupt downstream targets that potentially interfere with normal development.

“We could use our insight into this rare diagnosis to track down causes for much more common birth defects and intellectual disability,” said Dr. Krantz.

Translating Research Into Future Treatments

The study team is not only concentrating on identification of the causes of birth defects, but they also hope to uncover ways to treat them. Since we have two copies of all of our genes — one set inherited from our mother and one set inherited from our father — when one copy of the NIPBL gene is mutated, it results in CdLS, even though there is still another normally functioning copy. Since one mutated copy is sufficient to cause CdLS, the diagnosis follows an autosomal dominant pattern of inheritance.

The study team has shown that the normal copy of NIPBL tries to compensate for the deficient copy by increasing its level to make more normal acting NIPBL protein. If NIPBL expression levels fall below 50 percent, then the cells will likely die due to sister chromatid cohesion problems.

The study team suggests that if they can identify the regulatory mechanisms that allow the normal copy of NIPBL to somehow turn up its expression up from 50 percent to 60 or 70 percent, then perhaps they could test some drugs that could boost the gene’s expression to 80 to 90 percent and potentially help to correct some of the physiological differences seen in CdLS such as intellectual disability and slow growth.

“We’re hoping that the research will result in breakthroughs that we can then give back to the families and improve the outcomes of their children,” said Dr. Krantz.

Many families who have children with CdLS helped to establish an endowment for The Center for Cornelia de Lange Syndrome and Related Diagnoses, a “medical home” that provides multidisciplinary care for children with CdLS. Their goal is to fully fund the center with an endowment of $5 million, which will allow the Center to continue its remarkable progress in advancing novel diagnostic, management, and therapeutic tools through research.

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Community Scholar Project Addresses Needs of Gender Variant Youth


Transgender, gender non-conforming, and gender variant youth are often misunderstood or ignored when they try to get the attention of healthcare providers. Pediatrician and adolescent medicine specialist Nadia Dowshen, MD, founder and co-director of The Children’s Hospital of Philadelphia’s Gender and Sexuality Development Clinic, wants to help alleviate the frustration these marginalized youth experience by improving their access to health resources and services.

“This care is really a matter of life and death,” said Dr. Dowshen, who also is a faculty member at CHOP’s PolicyLab and serves as director of Adolescent HIV Services in the Craig-Dalsimer Division of Adolescent Medicine at CHOP. “Among people who are transgender, 40 percent have attempted to commit suicide at some point in their life, which are numbers that are staggeringly high. We need to do a better job of identifying who these youth are and offering support.”

In order to accomplish this, Dr. Dowshen has been selected to participate in the 2015-2016 inaugural cohort of the Community Scholars-in-Residence Program, a collaboration that includes CHOP and the University of Pennsylvania’s Community Engagement and Research Core, School of Nursing, Office of Inclusion and Diversity, Center for Public Health Initiatives, and the Implementation Science Working Group. The program is designed to provide exceptional junior faculty with dedicated time, mentoring, and support so that they can pursue research projects that cultivate engagement with community partners.

“The ultimate goals are to demonstrate that these kinds of resources and support can improve the quality and quantity of research funding, scholarship, and translation to improve population health,” said Karen Glanz, PhD, MPH, George A. Weiss University Professor and director of the UPenn Prevention Research Center. “This is a pilot program that we hope to build on for the future. We’re excited that our first cohort of Scholars includes Dr. Dowshen, who has already initiated productive research collaborations in the community.”

Over the next two years, Dr. Dowshen will work with the City of Philadelphia Department of Public Health’s Division of Maternal, Child, and Family Health (MCFH) to gain insights from the thoughts and experiences of transgender and gender non-conforming youth and other key stakeholders. She will use this information to increase healthcare providers’ knowledge and increase access to needed services.

“In order to develop programs and policies that will improve health outcomes among marginalized youth, I believe that our key stakeholders — the youth themselves and those in the community who work closely with them — need to be involved in all aspect of the research process in order for the research to be relevant and implementation of findings to be successful,” said Dr. Dowshen.

For the first part of the project, Dr. Dowshen and her colleagues at the MCFH will interview these adolescents, their parents, and community groups to identify and summarize their healthcare needs. The study team also will compile national policies that affect transgender and non-conforming youth and determine how they apply practically in the Philadelphia area. These steps will lead to the formation a community advisory board.

The second part will be to survey providers both throughout the CHOP Care Network and within the city health department clinics about their knowledge, attitudes, and practices with transgender and gender non-conforming youth. Based on the responses, Dr. Dowshen will identify focus areas for a curriculum to train the providers on ways that they can help to better care for this patient population.

“We know that when they do have the support of a multidisciplinary team of medical and mental health providers and a family and community, that gender non-conforming youth can grow up to be happy and healthy, productive adults,” said Dr. Dowshen.

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Research Needed to Address Health Needs of Adolescents With HIV


Every day Sarah M. Wood, MD, a fellow in the Craig-Dalsimer Division of Adolescent Medicine at The Children’s Hospital of Philadelphia, is stunned by the resilience and strength of the young people she works with who are living with HIV and the obstacles that they overcome. Yet, they have fallen into an extremely vulnerable space.

Currently, about 2.1 million adolescents worldwide are living with HIV. While recent data has shown that AIDS-related mortality declined from 2005 to 2012 for adults and children, adolescent mortality has increased by 50 percent. What is creating such a huge gap in treatment for adolescents?

In an editorial published in JAMA Pediatrics, Dr. Wood and colleagues suggest that adolescents living with HIV are a “generation at stake.” A significant barrier to achieving their optimal care is that youth with HIV who are older than 13 often are treated as adults, which fails to recognize that adolescence is a unique and distinct transition of physical, psychosocial, and neurocognitive development. These years also are a crucial time for youth who are not yet HIV positive but are at high risk for infection.

“They are still developing their brains, and they are subject to intense social pressures,” said Dr. Wood. “Those things can work together for youth who are not yet infected with HIV to increase their risk of becoming HIV positive through risk-taking behaviors. Or, for youth who have been born with HIV, their adherence to antiretroviral therapy is going to face significant challenges during this adolescent period.”

As an adolescent medicine expert, Dr. Wood recognizes that the concept of future orientation — teens’ ability to think about how poor adherence when they are feeling well will eventually impact their future health — is a difficult concept for most teens with chronic conditions to grasp. But that should not relegate the teen years as a tumultuous time of bad choices. Instead, she said, we must begin to prioritize adolescent HIV care as a “dynamic process of overlapping stages” and develop systems tailored to help youth navigate this continuum.

Then researchers can begin to pinpoint and pilot test interventions targeted at different levels of that cascade:

Dr. Wood is especially interested in exploring how to use and strengthen adolescents’ social support, which includes family, partners, and other people in their social network, to make improvements in these areas. Part of a program at CHOP called the Adolescent Initiative uses an integrated, medical case management model that emphasizes social support when helping youth to become more knowledgeable and competent in managing their HIV. Oftentimes, this means working with youth who have been left homeless due to stigma and discrimination related to their sexual orientation or gender identity.

“We’re doing work to optimize the social support that adolescents have because we can care for them while they’re in the clinic, but in the month or months in between when we see them, they must rely on the support that they have in their lives to be able to sustain treatment,” said Dr. Wood. “Many of our youth are thinking about where are they going to sleep that night and how are they going to eat. The stress of survival may outweigh their ability to think about taking a medication.”

Hearing firsthand from youth living with HIV about their daily difficulties has prompted Dr. Wood to pursue some important research questions: What factors in adolescents’ lives may challenge their ability to stay adherent to their therapy and stay suppressed from a viral load standpoint? And over time, how does housing, social support, substance abuse, and mental illness play into our ability to provide optimal care for youth living with HIV?

Another one of her research priorities is looking at ways to increase uptake of HIV pre-exposure prophylaxis.

“We live in an amazing time,” said Dr. Wood, who has 17 years of experience in the area of HIV and sexual health preventative care. “Keeping people adherent with their antiretroviral therapy can reduce their risk of transmitting to their partners. But we also now know that we can give antiretroviral medicine to our negative youth and keep them from becoming HIV positive.”

Prior to starting her Adolescent Medicine fellowship, Dr. Wood was a site investigator at CHOP for Project PrEPare, which aims to examine the acceptability and feasibility of daily medication to prevent HIV for young men who have sex with men. The study began in 2012 and included approximately 100 participants between the ages of 15 and 17 from 12 cities across the U.S. Now in its final stages, the project is a prime example of adolescent-specific research that will be essential to advancing HIV care and prevention for youth in years to come.

“We need to begin to build an adolescent care competent world in HIV,” Dr. Wood said.

Project PrEPare was organized by the Adolescent Trials Network for HIV/AIDS Interventions, a research network fund by the National Institutes of Health that develops and implements intervention trials for HIV positive and at-risk adolescents.

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Fresh Whole Blood Lowers Child Heart Surgery Exposure Risk


Infants and children who undergo heart surgery are better off receiving fresh whole blood transfusions from a single donor, compared to receiving component blood from multiple donors, according to new research from The Children’s Hospital of Philadelphia.

“Using fresh whole blood for transfusions reduces the number of individual blood donors to which patients are exposed,” said the study’s leader, David R. Jobes, MD, a cardiothoracic anesthesiologist in the Cardiac Center at CHOP. “The risks of transfusion reaction are most significantly linked to donors, so limiting such exposure will benefit patients.”

Well-recognized transfusion risks include allergic reactions, fevers, lung injury, and the transmission of infectious disease. Dr. Jobes and colleagues published their findings in the May 2015 issue of the Annals of Thoracic Surgery.

The research team did a retrospective study of 4,111 children receiving heart surgery at CHOP from 1995 to 2010. Of that number, 3,836 patients received fresh whole blood and 252 received only blood components. Since 1995, CHOP has provided fresh whole blood in heart surgery patients, relying on components only when whole blood was not available. Previous experience at CHOP had shown that using whole blood in heart patients reduced blood loss and lowered the need for subsequent transfusions.

In the current study, the median number of exposures was two donors, with higher numbers for younger patients having complex surgeries. For all the subgroups, the number of exposures was lower than amounts reported in scientific literature for pediatric cardiac patients who received blood components. The current practice in nearly all pediatric cardiac surgical programs is to rely solely on blood components.

“Many congenital heart conditions necessitate multiple surgeries beginning in infancy, and require multiple transfusions over a patient’s lifetime,” said Dr. Jobes, “so limiting donor exposures from the start may reduce long-term complications from blood transfusions.”

“We hope this research encourages officials to re-examine current blood storage practice and make logistical changes to make whole blood more readily available for pediatric heart patients,” Dr. Jobes added.

To learn more about cardiac care and research at CHOP, see the Cardiac Center website.

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Award Celebrates CHOP Expert’s Brain Tumor Research


At the 13th Annual Dream & Promise Gala, held May 27 in New York, the Children’s Brain Tumor Foundation honored The Children’s Hospital of Philadelphia’s Tom Curran, PhD, FRS, with the 2015 Fred J. Epstein, MD, Lifetime Achievement Award.

The award, which is named after the late Fred J. Epstein, MD, a pioneer in the field of pediatric neurosurgery, honors Dr. Curran’s work elucidating the molecular underpinnings of brain growth with an eye toward discovering novel treatments for pediatric brain tumors.

In particular, Dr. Curran’s work on medulloblastoma — the most common form of malignant brain tumor in children — led to the approval of the drug Erivedge (vismodegib). Approved to treat metastatic basal cell carcinoma, Erivedge is also being investigated as a treatment for a range of other cancers, from medulloblastoma to gliomas to colorectal cancer.

In addition to his position as Deputy Scientific Director of The Children’s Hospital of Philadelphia Research Institute, Dr. Curran is also a professor of Pathology and Laboratory Medicine in the University of Pennsylvania’s Perelman School of Medicine. Originally from Scotland, he received his PhD from London’s Imperial Cancer Research Fund Laboratories and University College before going on to a postdoc at the Salk Institute. He is a member of the American Academy of Arts and Sciences, the Institute of Medicine, and is a Fellow of the Royal Society.

Dr. Curran also helps lead the Children’s Brain Tumor Tissue Consortium (CBTTC). Founded with support from the CBTF, the CBTTC is a multi-institutional, collaborative research organization dedicated to the collection, annotation, and analysis of children’s brain tumors.

The CBTTC’s current work falls under four areas. Three projects are investigations of specific types of brain tumors — craniopharyngiomas, diffuse fibrillary astrocytomas, and ganglioglioma — while a fourth is focused on better understanding pediatric and adult gliomas. Much of the consortium’s work involves genomic sequencing, which is performed at Children’s Hospital in the BGI@CHOP sequencing facility.

“This award from the CBTF is a great honor, but it is really a recognition of the entire brain tumor team at the CBTTC — not just a single person,” said Dr. Curran. “Cooperation and sharing are the driving principles of the Children’s Brain Tumor Tissue Consortium.”

To learn more about the Children’s Brain Tumor Foundation, see their website. For more information about brain tumor-related research at CHOP, see the CBTTC site or the Center for Childhood Cancer Research.

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Thrombosis Researcher to Be Honored at ISTH Conference


The International Society on Thrombosis and Haemostasis (ISTH) is set to honor The Children’s Hospital of Philadelphia’s Sriram Krishnaswamy, PhD, at its annual meeting this summer. During the ISTH’s 2015 Congress, held in Toronto in June, Dr. Krishnawamy will receive a BACH Investigator Recognition Award for his work advancing our understanding of coagulation.

The Biennial Awards for Contributions to Hemostasis, or BACH, awards are given to researchers who “have made significant contributions to research and education in blood coagulation,” according to the ISTH site. Previous awardees include The Rockefeller University’s Barry S. Coller, MD, and Katherine A. High, MD, formerly of Children’s Hospital and now at Spark Therapeutics. Dr. Krishnaswamy’s fellow 2015 awardees include the University of North Carolina School of Medicine’s Nigel Mackman, PhD, and Timothy A. Springer, PhD, of Harvard University.

A thrombosis and hemostasis researcher, Dr. Krishnaswamy investigates the biochemical underpinnings of coagulation. In addition to his appointment at CHOP, Dr. Krishnaswamy is also a professor of Pediatrics in the University of Pennsylvania’s Perelman School of Medicine. Dr. Krishnaswamy’s work is supported, in part, by grants from the National Heart, Lung, and Blood Institute, including an R01 and a P01 to study the mechanisms of blood coagulation.

Dr. Krishnaswamy has led or contributed to numerous papers on the mechanics of coagulation and related topics. Last year he contributed to a Blood study led by Rodney M. Camire, PhD that examined the development of prothrombinase, the enzyme complex responsible for thrombin formation, an enzyme that plays a fundamental role in coagulation. By shedding light on the location of prothrombinase formation, the study lays the ground for future research.

More recently, his lab has been investigating specific blood coagulation factors, with an eye toward better understanding the factors’ structure and how they contribute to prothrombinase assembly. In one line of research, Dr. Krishnaswamy and colleagues are studying the venom of the eastern brown snake, pseudonaja textilis. One of the most venomous snakes in the world, the eastern brown snake is found in Australia and New Guinea.

Following previous work published in Blood, Dr. Krishnaswamy and his colleagues — including CHOP’s Shekhar Kumar, PhD, the University of Cambridge’s James Huntington, PhD — solved the x-ray structure of a protein in the venom of the eastern brown snake which is very much like the human coagulation factor Va. Despite having similar structures, the mammalian and reptile factors have radically different functions, functioning, respectively, as hemostatic agents and toxins. Overall, the researchers’ work is leading to a greater understanding of how coagulation factors operate.

To learn more about hematology research and care at The Children’s Hospital of Philadelphia, see the Division of Hematology.

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