Oct 01 2014

Safety of Severe Asthma Care Outside the ICU Assessed

asthmaClinicians at The Children’s Hospital of Philadelphia have extensive experience in treating children with acute asthma flares, partly due to the tremendous volume of patients with this respiratory condition who come from the urban community nearby. Asthma is one of the leading, serious, chronic illnesses among children in the U.S., and Philadelphia ranks among the top 5 worst asthma cities.

During an asthma exacerbation, a child’s lungs and airways overreact to a certain trigger. The airways’ lining swells, and muscles surrounding the airways constrict. As these air passages narrow and become clogged with mucus, the child’s breathing becomes difficult, as if trying to get air through a pinched straw.

About 2,700 patients are admitted for asthma in a given year at The Children’s Hospital of Philadelphia, accounting for 17 percent of the total admissions. When a child with a severe asthma flare arrives at the emergency room, clinicians initiate one hour of continuous aerosolized albuterol (CAA), a quick-acting beta-agonist bronchodilator, in addition to other therapies, to relieve the patient’s shortness of breath.

If the flare is very severe, clinicians will continue continuous medication delivery when the patient is admitted to the hospital, which in many hospitals occurs in the intensive care unit. Because asthma is such a prevalent pediatric condition, often a patient with severe asthma occupies an intensive care unit (ICU) bed that is in high demand.

Chén Kenyon, MD, an attending physician in the Division of General Pediatrics at CHOP, and colleagues, wanted to find out if these patients are treated safely and effectively with CAA in the non-ICU, inpatient setting, which may free up limited ICU beds for other high acuity patients and offer significant cost-savings. Unfortunately, no published scientific data existed to support this practice, so to begin to answer the question, they conducted a retrospective cohort analysis of electronic medical record data using the CHOP Data Warehouse.

“Using this unique resource, we are able to provide much more granularity than prior studies,” Dr. Kenyon said. “We can pinpoint physician orders and see at what point a particular therapy was ordered and when it was stopped.”

A clinical pathway in place for 18 years at CHOP helps clinicians to streamline and standardize asthma care. It includes a component that allows for CAA to be administered in the non-ICU, inpatient setting for patients with severe asthma who are assessed hourly by trained respiratory therapists and nurses. The researchers combed through physician orders for CAA of 1,300 children ages 2 to 18 treated under this protocol from July 2011 to June 2013. They compared the cohort to 1,700 patients who received intermittent albuterol only and assessed the two groups’ characteristics and rate of adverse outcomes. Results from the study appeared online Sept. 29 in Pediatrics.

“There seemed to be no difference in the prevalence of low potassium or cardiac arrhythmia, two side effects associated with beta-agonists in rare situations,” Dr. Kenyon said. “While patients who received continuous aerosolized albuterol had a higher rate of transfers to the ICU, there was no difference in the rate of intubation. Zero patients in the continuous aerosolized albuterol group were intubated. These findings support the safety – and efficacy – of continuous aerosolized albuterol delivery in the non-ICU setting.”

The researchers also determined that certain factors identified initially in the emergency room predicted which patients would go on to deteriorate clinically and require prolonged therapy. These included comorbid pneumonia and administration of intravenous magnesium or subcutaneous terbutaline in the emergency room. Being acquainted with these characteristics may help clinicians in hospitals without a pediatric intensive care unit (PICU) in terms of recognition of patients at higher risk for clinical deterioration who may benefit from relocation to an institution that does have a PICU, Dr. Kenyon said.

While this retrospective study sets the stage for other hospitals to evaluate how CAA could fit within the context of their asthma protocols, Dr. Kenyon emphasized that CHOP’s success in CAA delivery outside the ICU is, at least in part, due to the support structure and care processes in place. For example, in addition to the standard nurse to patient ratio of 1 to 4 and robust expert respiratory therapy support, a critical assessment team assists front-line providers in the care of patients with severe asthma who have early signs of clinical deterioration.

“This is a first step,” Dr. Kenyon said. “There is still work to be done to figure out who the ideal cohort is for continuous therapy and what resources are necessary to make this practice safe and effective in a non-ICU setting outside of CHOP. But this study provides initial evidence for the safety and effectiveness for institutions that already are providing continuous aerosolized albuterol on their non-ICU units.”

Future studies could aim to reproduce a similar study on a multicenter level, Dr. Kenyon suggested. Researchers could perform further analysis of the data to reveal any potential cost savings that may be associated with centering CAA delivery for severe asthma cases outside the ICU. More evidence also is needed to determine the appropriate length of CAA administration, and if other modes of therapy could help to enhance patients’ recovery so that they spend less time in the hospital.

Permanent link to this article: http://www.research.chop.edu/blog/safety-severe-asthma-care-outside-icu-assessed/

Sep 29 2014

Antibiotic Use in Infancy May Play Role in Obesity

obesityWhile it is easy to blame the childhood obesity epidemic on too many french fries and video games, it is likely that multiple factors such as genetics and environment also contribute to excessive weight gain. A retrospective study based on data from The Children’s Hospital of Philadelphia’s electronic health records identified another significant risk factor that may influence how tendencies toward obesity develop during infancy.

Childhood obesity has more than doubled in children over the past 30 years, according to the Centers for Disease Control and Prevention. Many will remain obese into adulthood and be susceptible to heart disease, type 2 diabetes, stroke, several types of cancer, and osteoarthritis. Medical researchers at CHOP want to identify ways to intervene as early as possible, in order to avert the lifetime of medical, developmental, and social problems associated with obesity.

They were intrigued by the emerging idea that the microbial population that begins to colonize in infants’ intestines shortly after birth, known as the microbiome, plays an important role in establishing energy metabolism. Previous studies have shown that antibiotic exposure influences the microbiome’s diversity and composition.

“As pediatricians, we’re interested in whether there is anything happening early in life that resets this ‘thermostat’ and has a long-term effect on how your body regulates its weight,” said L. Charles Bailey, MD, PhD, lead author of the study that appeared online Sept. 29 in JAMA Pediatrics. “The thought is that the microbiome may be critically dependent on what is going on during infancy.”

Dr. Bailey and colleagues observed an increased risk of obesity with greater antibiotic use, particularly for children with four or more exposures to broad-spectrum antibiotics in early childhood. The study team analyzed electronic health records from 2001 to 2013 of 64,580 children with annual visits at ages 0 to 23 months, as well as one or more visits at ages 24 to 59 months within the network of primary care practices affiliated with CHOP. They assessed the relationships between antibiotic prescription and related diagnoses before age 24 months and the development of obesity in the following three years.

“What this study is showing is that we can detect a connection between the antibiotics that you may have received as an infant and what your weight is going to look like later in childhood,” Dr. Bailey said, adding that it is important to note that the study does not directly examine cause and effect.

obesityThe investigators saw the association with broad-spectrum drugs, but they reported no significant association between obesity and narrow-spectrum drugs. For this study, they classified first-line therapy for common pediatric infections, such as penicillin and amoxicillin, as narrow-spectrum. They considered broad-spectrum antibiotics to include those recommended in current guidelines as second-line therapy.

“What we think we’re seeing here with these associations is that the more we choose to use narrow-spectrum antibiotics, the less likely it may be that we’re doing something that will affect a patient’s risk of obesity later on,” Dr. Bailey said.

One of the study’s advantages is that the researchers capitalized on CHOP’s wealth of information captured during regular medical care for a large group of patients without compromising individuals’ privacy. While the study did not assess children’s activity levels, dietary habits, family structure, or socioeconomics, the researchers’ conclusions were similar to those from a previous study that evaluated those factors and also found a connection between antibiotics in early childhood and higher risk of obesity.

Future investigations are needed involving multiple large pediatric health systems that will take a broader look at several populations and how adopting guidelines that accentuate the use of narrow-spectrum antibiotics might affect patients’ risk of obesity, Dr. Bailey said.  In addition to supporting this type of research locally, CHOP is also a key contributor to networks such as PEDSnet that link many children’s hospitals to make more effective clinical research possible.

Researchers also are looking at ways the microbial communities living in infants’ intestines are swayed by dietary and environmental factors. The Children’s Hospital of Philadelphia’s Healthy Weight Program has a study underway that is following the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain. As part of the study, they will track any babies who are prescribed antibiotics, in order to identify fluctuations in their microbial profiles.

Such research projects will add up to help give clinicians practical guidance on how to address the complexities of obesity.

“Treating obesity is going to be a matter of finding the collection of things that together have a major effect, even though each alone has only a small effect,” Dr. Bailey said. “Part of what we are exploring in this study is one of those factors that we can possibly modify in the way we take care of kids and make it better.”

Christopher Forrest, MD, PhD; Peixin Zhang, PhD; Thomas M. Richards, MS; Alice Livshits, BS; and Patricia DeRusso, MD, MS, contributed to the article published in JAMA Pediatrics. The American Beverage Foundation for a Healthy America provided an unrestricted donation to support this Healthy Weight Program research study.

Permanent link to this article: http://www.research.chop.edu/blog/antibiotic-use-infancy-may-play-role-obesity/

Sep 26 2014

Basic Research Invests in Our Future

We just had to share this great video explaining how supporting basic research can lead to unforeseen breakthroughs in the future. Winner of the second annual Federation of American Societies for Experimental Biology (FASEB) “Stand up for Science” competition, the video was produced by a group of young Bay Area researchers, and is a call to support basic research funding.

“Basic research is an investment in our future. It broadens our understanding of the world we live, and the potential benefits are limitless,” the video states.

While the NIH’s funding may seem impressive—in the 2015 budget the agency is allotted $30.2 billion, a slight increase over 2014—that number is somewhat misleading. Adjusted for inflation, the 2015 budget would be $100 million lower than the 2002 funding level for the NIH. Therefore messages like the one in this video, which does a great job of explaining why scientific research needs your support, are more important than ever. Enjoy!

Permanent link to this article: http://www.research.chop.edu/blog/basic-research-invests-future/

Sep 24 2014

Investigators Take Clinical Look at Teen Driver Safety

teen driver safetyCrashes remain the leading cause of young adult death (ages 16 to 24) with four times the number of deaths from cancer and 38 times the number of deaths from the flu. In fact, a teen’s highest lifetime risk of crashing occurs immediately following the learner phase when beginning to drive without adult supervision.

A team of researchers at The Children’s Hospital of Philadelphia Research Institute’s Center for Injury Research and Prevention (CIRP), led by Flaura Koplin Winston, MD, PhD, is taking a new tactic by addressing novice drivers’ performance and risk management from a clinical standpoint.

“As a primary care pediatrician at Karabots, I see my role as helping families to anticipate and manage health issues and ensure their children can realize their full potential,” said Dr. Winston, scientific director and founder of CIRP. “When my research showed that motor vehicle crashes accounted for one-third of all teen deaths, I looked for protocols to include driving management in my practice, but I couldn’t find them. I could not even find a valid way to assess driving performance and risk.

“This is when I knew that CHOP could take a lead on bringing our science to bear in evidence-based, evaluated ways to help families manage this exciting but dangerous phase of an adolescent’s life,” Dr. Winston continued. “Each teen approaches the driving task with assets as well as challenges, and once we figure out what they are, then we can put into place a personalized care management plan.  Driving has a relatively small margin for error, and I want to do what I can to ensure that adolescents safely navigate the transition from childhood to adulthood — from the car seat to the driver’s seat.”

CIRP experts have spent many hours dissecting the factors behind why teens crash and what skills new drivers are missing. They compiled research and evidence-based practice about the major constructs around safe driving behavior. Team members also mined a massive database called the National Motor Vehicle Crash Causation Survey, and they identified the most common crash scenarios involving teen drivers.

teen driver safety

“Each teen approaches the driving task with assets as well as challenges, and once we figure out what they are, then we can put into place a personalized care management plan.” – Dr. Flaura Koplin Winston

Their work has led to the innovative concept of developing a systematic method for diagnosing driving skill level as a crucial step in personalized driving management plans. The first phase of their work is nearly complete: The team has built and validated an initial version of a Simulated Driving Assessment (SDA) tool that uses a high fidelity driving simulator located at CIRP to achieve realistic reproductions of driving experiences and conditions.

Study participants are exposed to a series of “drives” that involve variations of three main crash scenarios during a 35- to 40-minute session. The researchers collect and analyze data on numerous aspects of the drivers’ performance — from steering and braking reaction times to eye movement and headway time — and can produce an automated report.

“Some teens may have trouble with attention; some may have trouble with hand-eye coordination; some may not have the cognitive skills needed to drive safely; and due to inexperience, most have skill deficits,” Dr. Winston said. “By diagnosing driving, we want to tease out what driving deficits a teen might have before he or she crashes.”

Having a mechanism in place that gives clinicians and parents a better sense of whether or not teens are ready for independent driving is especially important in states like Pennsylvania that have laws requiring physicians to medically certify that a patient is fit to drive. If a teen has some type of medical condition that could impair his or her ability to safely operate a motor vehicle, physicians are mandated to report it to the Pennsylvania Department of Transportation.

As the CIRP team gains more experience at determining which teens could benefit the most from the SDA, Dr. Winston’s future dream is to establish a driving clinic at CHOP. Physicians could refer patients to the clinic for screening, and based on the driving diagnosis, young drivers would receive recommendations or training to help improve their performance on the road. Already, the CIRP team has published findings that show novice drivers benefit from web-based training programs that expand the diversity of the teens’ driving practice.

“CHOP is at the forefront of teen driver safety research, and it is an amazing place to take these leaps because of our interdisciplinary nature,” Dr. Winston said. “Generous funding from the Pennsylvania Department of Health allowed us to get the driving simulator and put us in a unique position to address the leading cause of death for teens.”

The CIRP team is encouraged by interest from other potential partners who support this urgently needed line of research and are looking for sponsorship to making a driving clinic at CHOP a reality.

Permanent link to this article: http://www.research.chop.edu/blog/investigators-take-clinical-look-teen-driver-safety/

Sep 22 2014

Healthy Weight Program Launches Study on Microbiome

microbiomeTrillions of naturally occurring bacteria and other microbes coexist in the human gut and are part of how we process food and harness energy. Known as the microbiome, this complex collection’s potential role in early weight gain and obesity has become a fascinating area of scientific exploration.

Approximately 10 percent of children in the U.S. are already obese by age 2. These rates are especially concerning because research suggests that infants with rapid growth during the first two years of life may be more likely to be obese later in childhood and into adulthood. Excessive weight gain in childhood is associated with elevated blood pressure, musculoskeletal complaints, and asthma.

An interdisciplinary study team from The Children’s Hospital of Philadelphia and University of Pennsylvania has begun an observational cohort study that will focus on the role of the gut microbiome in the development of obesity early in life. It is a unique research opportunity because babies are born with close to sterile conditions, but they are quickly colonized with the microbes that they are exposed to in their environment.

“We are enrolling moms during their third trimester and trying to characterize their vaginal and gut microbiota, look at the transmission to infants, and follow the changes of the microbiota of infants through the first year of life to see if it correlates with weight gain,” said Babette S. Zemel, PhD, principal investigator of the Infant Growth and Microbiome (I-gram) study. “We are focusing on low-income African American families because they have the highest rates of obesity in adulthood in the U.S. We want to try to tackle this problem early if we can.”

Not only will the researchers consider the microbiome in this long-term study, but they also will have the opportunity to simultaneously investigate a number of other risk factors associated with obesity. For example, epidemiological evidence suggests that children born by cesarean section have higher rates of obesity than those who are born vaginally. This points to the hypothesis that infants who miss out on early transmission of maternal microbiota could be more susceptible to excess weight gain in childhood.

In a subset of babies, the researchers plan to observe how rapidly the infants’ microbial communities cultivate. For another subset, they intend to track any babies who are prescribed antibiotics, in order to identify fluctuations in the microbial profiles after the infants receive the medications and to see how quickly the microbes are restored.

“Fluctuations in microbial profiles could support a mechanism for the association between antibiotics and early obesity,” said Patricia DeRusso, MD, MS, director of the Healthy Weight Program at The Children’s Hospital of Philadelphia.

An additional focus of the I-gram study will be to examine the role of multiple feeding-related factors including breastfeeding, formula feeding, sucking behavior, feeding patterns, and timing of introduction of solid foods.

Looking at the potential interaction of these novel mechanisms will help to create a detailed description of what happens in the first year of life among infants born to 300 normal weight vs. obese African American, predominantly low-income mothers. The moms will give birth at the University of Pennsylvania where study collaborators will collect samples at the time of delivery. Next, infant growth experts at CHOP will measure the infants and follow their development carefully over the next 12 months. They will use a machine called a Pea Pod to periodically measure the infants’ body composition — the amount of fat and lean tissue in the body.

“The long-term implication of this study is that if we can identify early predictors of weight gain during infancy, it is an ideal opportunity to intervene in some way,” Dr. Zemel said.

Interest in the microbiome has flourished as better tools have emerged that allow scientists to analyze the microbes’ DNA and their metabolic byproducts, which are an essential part of our digestive system. Intriguing research suggests that people who are obese have a different profile of microbiota than people who are not obese. Dr. Zemel pointed out that findings from a study of twins, in which one twin was obese and the other was not, demonstrated that a fecal microbiota transplant from the obese twin into germfree mice resulted in weight gain for the rodents.

“This adds to the evidence that there is some causal link between the gut microbiome and the development of obesity,” Dr. Zemel said.

The I-gram study is one of 10 research projects in the portfolio of CHOP’s Healthy Weight Program that aim to advance understanding of the root causes of obesity and effective models for prevention and treatment, focused on early childhood intervention.  Funding was provided by an unrestricted donation from the American Beverage Foundation for a Healthy America to The Children’s Hospital of Philadelphia to support the Healthy Weight Program.

“Obesity prevention is a signature area of our research,” said Gurpreet Kalra, MS, CCRP, research program manager for the Healthy Weight Program. “Our agenda is informed by the latest Institute of Medicine’s guidelines that stressed the lack of research on obesity prevention in very young children. Identification of novel, modifiable risk factors, which is the focus of the I-gram study, is key to obesity prevention.”

The portfolio has a comprehensive focus because obesity is a complex, multifactorial disease and uses a variety of electronic health records, social media, and community partnered strategies to conduct the research.

“We are committed to long-term studies that can more conclusively prove causality and test the effectiveness of interventions,” Gurpreet said.

Most of the studies involve children and families from neighboring high-risk populations and communities where obesity rates are among the highest in the city. The multidisciplinary investigative team includes experts in anthropology, pediatric and adult gastroenterology, endocrinology, psychology, psychiatry, obstetrics and gynecology, microbiology, genetics, public health, and biostatistics.

Permanent link to this article: http://www.research.chop.edu/blog/healthy-weight-program-launches-study-microbiome/

Sep 19 2014

Gene Mutation Helps Explain How Our Body Clock is Set

sleepMost of us have failed to get enough sleep on a few occasions. Maybe it was as a college student studying for final exams, or as a new parent consoling an infant who is teething. Remember how you dragged through the next day in a bad mood and unable to focus?

Yet, a few people who are considered to be natural “short sleepers” seem to function well under the same sleep-deprived circumstances. Researchers at The Children’s Hospital of Philadelphia are investigating why some of us seem to need more sleep than others.

In a study published in the August issue of SLEEP, the study team described a new gene variant associated with short sleep and resistance to sleep deprivation in humans. Their findings support the hypothesis that genes related to circadian rhythms, in particular DEC2, can affect not only the timing of sleep, but also the magnitude of sleep homeostasis and sleep architecture.

Circadian rhythms control the biological clocks in our bodies. Homeostasis includes both short-term and long-term measures that the body uses to control and maintain an optimal internal environment.

“We found DEC2 is not only a circadian gene, but it is also related to homeostasis,” said Renata Pellegrino, PhD, senior research associate in the Center for Applied Genomics at The Children’s Hospital of Philadelphia, who collaborated on the study with an international study team. “That is why we are so excited. This gene could explain sleep length and how we respond to sleep deprivation, or why some of us sleep for a certain number of hours a night and others don’t.”

The researchers sequenced circadian clock genes in a cohort of healthy young adult twin pairs with no chronic conditions. Out of 200 twins, they identified a DEC2 mutation in one sibling who during baseline testing slept an average of five hours per night — more than an hour shorter than his twin brother who did not carry the gene.

The study team performed a series of cognitive performance tests to see how attentive each brother was after spending 38 hours without sleep in the sleep lab. The twin with the gene mutation performed better on psychomotor vigilance compared to his brother.

During unrestricted recovery sleep for one night following the 38 hours without sleep, the twins underwent electroencephalography that showed their brains’ electroactivity throughout the major sleep phases — Stages 1, 2, 3, 4 and REM. Stage 3 is characterized by Delta waves, which are high amplitude brain waves associated with deep, restful sleep. Stage 3 sleep also is related to maintaining homeostasis after sleep deprivation or wakefulness. The twin with the DEC2 mutation made more Delta waves and stayed in Stage 3 sleep longer than his brother.

The researchers went a step further to investigate how the DEC2 mutation interacted with other circadian clock genes. They discovered that the variant appears to alter the molecular mechanisms that set the duration of sleep that individuals need.

In the future, Dr. Pellegrino and her colleagues plan to form collaborations with researchers in other countries to see how common this variant is in other populations. They also would like to discover how the genes not only affect the brain, but also other body systems.

“True short sleepers in general are very resistant to sleep deprivation,” Dr. Pellegrino said. “They are very motivated and ready to go, so maybe the mutation protects you cognitively. But is there a price for that? We still don’t know the other metabolic effects.”

The study involved a collaboration among researchers from The Children’s Hospital of Philadelphia; the University of Pennsylvania School of Medicine; the Philadelphia Veterans Affairs Medical Center; Washington State University; Universidade Federal de Sao Paulo, Brazil; and Koc University, Istanbul, Turkey. The research was supported in part by grants from the National Heart, Lung, and Blood Institute, and the Institutional Development Fund from the Center for Applied Genomics at CHOP.

Permanent link to this article: http://www.research.chop.edu/blog/gene-mutation-helps-explain-body-clock-set/

Sep 17 2014

Get Involved to Make Medical Research a National Priority

medical researchIt’s your turn to give a shout-out for scientific discovery. The Rally for Medical Research Capitol Hill Day Thursday, Sept. 18, brings together almost 300 national organizations, including The Children’s Hospital of Philadelphia, in support of making funding for the National Institutes of Health (NIH) a national priority.

Programs like those at The Children’s Hospital of Philadelphia Research Institute need a reliable stream of revenue in order to conduct the long-term scientific projects that ultimately produce breakthrough treatments and cures for diseases.

Since 2003, the NIH budget has declined by more than 22 percent, or $6.1 billion, after adjusting for inflation, according to the Association of American Medical Colleges (AAMC), a rally day sponsor. The AAMC developed a set of advocacy materials to help the medical and research communities to urge Congress to pass the FY 2015 Labor, Health and Human Services, Education, and Related Agencies (Labor-HHS) spending bill and restore funding to NIH cut by sequestration in 2013. A draft of the bill provides $30.5 billion for NIH, a $606 million (2 percent) increase over FY 2014.

What can you do? Send a letter to members of Congress through the AAMC’s legislative action center telling you representatives that NIH is critical to the advancement of science and improving the health of people around the world. You can add a personal message about your research experience, what you hope to accomplish, or what inspires your research career.

Share tweets and posts encouraging your fellow scientists, medical trainees, graduate students/post docs to call Congress to action. Here’s an example:

Federal funding for medical research is the way we protect our nation’s health. Act now: http://owl.li/BeHF9 #FinishtheJob

Support the AAMC’s Thunderclap campaign, which is a “crowdspeaking platform” that will post a message Thursday to the social media accounts of participants asking their friends and followers to also send a letter to Congress to pass the Labor-HHS bill. The AAMC hopes to generate thousands of letters in support of the federal investment in medical research. Get involved: The louder the thunder, the greater the impact.

Permanent link to this article: http://www.research.chop.edu/blog/get-involved-make-medical-research-national-priority/

Sep 15 2014

Scholar Hope Grant Supports Neuroblastoma Research


©2014 Paul Crane, Crane Photography, Inc.

Pediatric oncology researchers at The Children’s Hospital of Philadelphia are driven to find new treatments for childhood cancer, and the Hyundai Hope On Wheels program is supporting their hard work by awarding a 2014 Scholar Hope grant to help fund investigations that focus on the aggressive form of neuroblastoma. Despite intense treatment, more than 50 percent of children with high-risk neuroblastoma die of their disease, accounting for 12 percent of pediatric cancer deaths.

Kristina Cole, MD, PhD, a CHOP attending physician and researcher with expertise in identifying therapeutic targets in pediatric cancer, received the Scholar Hope grant at a “Handprint Ceremony” in front of the hospital Sept. 11. Children from the oncology floor were invited to place their handprints in paint on a Hyundai car that is traveling across the country to build awareness of pediatric cancer research. Hyundai Motor America and its more than 820 U.S. Hyundai dealers have donated more than $86 million to pediatric cancer research in the U.S. through Hope On Wheels.

Each child’s handprint stands out as one of a kind, as does Dr. Cole’s novel research project which aims to demonstrate, for the first time, that a subset of patients with neuroblastoma could benefit from checkpoint inhibition and support further clinical development of new generation checkpoint inhibitors for pediatric solid tumors.

In previous work, Dr. Cole and colleagues have shown that neuroblastoma tumors rely on the DNA repair checkpoint protein kinase 1 (CHK1) to handle the cellular stress caused by the powerful MYCN oncogene that drives tumor growth. When CHK1 is inhibited, the neuroblastoma cells can no longer grow and die. Several clinical trials are underway based on the idea that if cancer cells are exposed to a CHK1 inhibitor, the protein will be unable to respond when the cell’s DNA is damaged by treatments such as chemotherapy.


©2014 Paul Crane, Crane Photography, Inc.

“This current research is unique because we’re trying to better understand which patients may benefit and why they may benefit,” Dr. Cole said. “We think that MYCN certainly has a very large role, but is it possible that other factors — like underlying defects in genes that mediate DNA damage — make certain patients even more likely to benefit from this treatment strategy.”

First, researchers will analyze large genomic datasets from hundreds of primary tumor samples to find any defects in DNA repair genes. Then, they will characterize how those mutations could make neuroblastoma tumors more sensitive than other tumor types to drugs that inhibit CHK1. Their third aim will be to do preclinical work in the laboratory with cell cultures and animal models to be able to justify a clinical trial of next generation checkpoint inhibitors in combination with traditional chemotherapy.

The researchers’ hypothesis that certain neuroblastoma tumors have increased dependency on the compensatory DNA repair pathway due to a possible defect in DNA repair genes is reminiscent of what has been described in breast cancer research, Dr. Cole said. Breast tumor cells with inherent DNA repair defects, such as mutations in BRCA1 or BRCA2, are sensitive to drugs that inhibit PARP, another protein that helps cancer cells repair DNA damage and survive. Tumor cells with normal BRCA proteins continue to grow.


©2014 Paul Crane, Crane Photography, Inc.

Dr. Cole is among 36 Scholar Hope two-year grant winners, who each received $250,000 for a total of $9 million in support. The ultimate goal of the Scholar Hope grant program is to find cures for childhood cancers once and for all, according to the program’s website.

“It is a great award that they’ve put together to support the work done by individuals from Children’s Oncology Group institutions all across the country who are investigating pediatric cancers,” Dr. Cole said. “They’ve been very generous to CHOP.”

Permanent link to this article: http://www.research.chop.edu/blog/scholar-hope-grant-supports-neuroblastoma-research/

Sep 12 2014

Researchers Explore Girls’ Response to Breast Cancer Risk

breast cancerThis is the first generation where women are routinely tested for genetic mutations that may increase their risk for breast cancer. They are also increasingly aware of the implications of their cancer history and genetic testing results on their daughters.

Researchers at The Children’s Hospital of Philadelphia are collaborating with adult breast cancer specialists to find ways for girls from high-risk families to navigate the nuances of how growing up with this knowledge affects their well-being and health behaviors.

One in 8 women in the U.S. will develop invasive breast cancer during their lifetime, according to the American Cancer Society. It is estimated that 5 to 10 percent of breast cancer cases result directly from gene defects — usually a mutation in the BRCA1 and BRCA2 genes — inherited from a parent.

Yet little research has been completed that explores how adolescent girls understand and respond to learning about their familial breast cancer risk, and many pediatric practitioners are inexperienced in helping them to deal with a legacy of cancer. Lisa A. Schwartz, PhD, a psychologist in the Division of Oncology at CHOP, is involved with two studies that are addressing this knowledge gap: “Studies of Female Teens” (SOFT I and SOFT II) and “Lessons in Epidemiology and Genetics of Adult Cancer from Youth” (LEGACY Girls Study).

“We want to capitalize on this window of time during the transition to adulthood when health behaviors are being solidified, and provide guidance on how they value their health and how they fit health into their identity as it’s being developed,” Dr. Schwartz said.

She works closely on this research with co-principal investigators Angela R. Bradbury, MD, an assistant professor of medicine in the Division of Hematology-Oncology at the Perelman School of Medicine at the University of Pennsylvania, and Mary B. Daly, MD, PhD, at Fox Chase Cancer Center. Dr. Bradbury presented some of the SOFT II study’s findings in June at the annual meeting of the American Society of Clinical Oncology.

The study involved 320 girls with an average age of 15 years who were classified as either “high risk” or “population risk.” High-risk girls had a parent with a BRCA1/2 mutation or at least one first-degree or second-degree relative with a history of breast cancer. The results showed that high-risk girls were almost three times more likely to worry about breast cancer than population-risk girls, even when their mothers’ had no history of the disease. The study, which caught the attention of public media provider NewsWorks, also revealed that high-risk girls were significantly more likely to smoke cigarettes.

“We don’t know how to interpret that yet,” Dr. Schwartz said. “Is it because the anxiety is driving them to want to self-medicate, or is it because they have a fatalistic attitude that they’re going to get cancer anyway?”

The study team encouraged future research projects to evaluate outcomes of disclosure of genetic breast cancer risk to adolescents. Dr. Schwartz, Dr. Bradbury, and co-investigator Linda Patrick-Miller, associate director of the Center for Clinical Cancer Genetics at the University of Chicago, covered this emotionally charged topic in a presentation about sharing genetic information with offspring at the international conference Joining FORCEs Against Hereditary Cancer held in Philadelphia June 12-14.

Current National Comprehensive Cancer Network guidelines call for breast cancer surveillance for high-risk patients to begin with monthly self-exams at age 18, but semiannual clinical breast exams and annual mammograms are not recommended until age 25. Some contend that adolescents do not need to have immediate knowledge about their familial breast cancer risk since they do not undergo screening tests until adulthood. On the flip side, others advocate for disclosure in the teen years because young women can take steps to reduce their risks and practice healthy lifestyles as early as possible.

“Knowing your risk probably is a positive thing, but we’re not doing a good job of helping teens to manage that risk,” Dr. Schwartz said. “We don’t just want to leave these girls worrying and then turning to bad behaviors because they’re afraid that they have no choices. We can reframe this risk and help them to see that they can have control over their health.”

In light of the sensitive nature of their studies that recruited vulnerable adolescents, Dr. Schwartz participated with colleagues to implement an event monitoring committee to provide additional oversight of their research activities as a safeguard to identify any emotional, social, cultural, or economic issues that might develop. The study team published their framework and recommendations in the Journal of Adolescent Health for other investigators and institutional review boards to incorporate into future regulatory standards to improve the safety of behavioral and observational studies involving children and adolescents.

“When working with children and families, it’s important to really think through and identify any precautions that you can take in your research to protect them,” Dr. Schwartz said.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-explore-girls-response-breast-cancer-risk/

Sep 08 2014

Study Aims to Reveal Novel Drivers of Allergic Disease

allergic disease

This strategy is an exciting alternative to current treatments for allergic disease that globally shut down immune function, Dr. Oliver said.

Chronic allergic disorders affect millions of individuals worldwide, and their frequency is increasing, especially in children and adults living in the U.S. Often, multiple allergic diseases, such as asthma, food allergies, atopic dermatitis, and some gastrointestinal disorders can occur in a single patient.

Investigators at The Children’s Hospital of Philadelphia are studying the underlying biological features that could be common from one allergic disease to another. In particular, they are interested in how two small adapter proteins, Ndfip1 and Ndfip2, activate enzymes called E3 ubiquitin ligases that could play an important role in preventing allergic disease.

“A small protein, ubiquitin, is the basis for the garbage disposal system of the cell,” explained Paula M. Oliver, PhD, in the Cell Pathology Division of CHOP and an associate professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine. “When ubiquitin is tagged to a protein, one of the outcomes can be degradation of that protein. So it is the cell’s way of removing unneeded proteins. When you don’t get rid of those proteins, you can get allergic disease.”

Dr. Oliver’s study team is using genetically engineered mice to study E3 ubiquitin ligase function. They previously have shown that mice in which a particular ligase — aptly named ITCH — cannot function, develop an allergic dermatitis-like phenotype that causes them to scratch. They also get inflammation of the lungs that is reminiscent of asthma and gastrointestinal disorders that have features similar to food allergies.

In Dr. Oliver’s current work that received funding in July from the National Institute of Allergy and Infectious Diseases, the investigators already have figured out how E3 ubiquitin ligases remain inactive in a closed, “off” position until Ndfip1 and Ndfip2 seem to open them up and turn them “on.”

“We took the next step in thinking that maybe there are some ways of forcing that to happen and turn on these enzymatic pathways in cells to prevent or treat allergic disease,” Dr. Oliver said.

This strategy is an exciting alternative to current treatments for allergic disease that globally shut down immune function, Dr. Oliver said. The new approach they are studying would disarm only the component of the immune system that drives allergic responses, while not affecting its ability to respond to viruses or pathogenic bacterial infections.

Over the next year, the study team will move toward developing therapeutic methods to regulate E3 ubiquitin ligase activation. They will design small penetrating peptides aimed at catalyzing the transfer of ubiquitin to a substrate protein in the cell. They also will work with a local company to create small molecule activators of the ligases, as a second possible approach.

“We are quite sure that there are other mechanisms that might control these things as well, so we’re continuing to understand exactly how this happens,” Dr. Oliver said. “We’re also trying to understand what the substrates are that need to be gotten rid of because that might tell us more about how allergic diseases start or which proteins are important in driving allergic diseases.”

In addition to receiving funding from the NIAID, Dr. Oliver’s work is supported by the American Asthma Foundation.

Permanent link to this article: http://www.research.chop.edu/blog/study-aims-reveal-novel-drivers-allergic-disease/

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