Feb 04 2015

CHOP Invited to President Obama’s Precision Medicine Announcement

precision medicineAt the invitation of the White House, last week The Children’s Hospital of Philadelphia sent two special guests to President Barack Obama’s announcement of the Precision Medicine Initiative: Steven M. Altschuler, MD, CHOP’s chief executive officer, and 9-year-old CHOP patient Emily Whitehead, who is cancer-free thanks to a personalized treatment called T cell therapy developed at CHOP.

The Precision Medicine Initiative, which President Obama first announced in his 2015 State of the Union speech, calls for new funding to build a national infrastructure to help sophisticated biomedical data flow from health clinics to DNA sequencing labs and back again as innovative treatments.

Precision medicine offers “one of the greatest opportunities for new medical breakthroughs that we have ever seen,” President Obama said.

The National Institutes of Health, Food and Drug Administration, and the Office of National Coordination for Health Information Technology will be involved in this program, which would allow researchers to custom-design more effective therapies based on a patient’s individual genetic profile.

“I am thrilled that President Obama recognizes the promise of our nation’s research efforts by making this investment. This announcement signifies his commitment to bringing this issue to the forefront of our national agenda,” said Dr. Altschuler.

Emily Whitehead, of Philipsburg, Pa., was diagnosed with acute lymphoblastic leukemia (ALL) at the age of four. After multiple relapses, she was out of standard treatment options. In 2012, she became the first child to enroll in the clinical trial for T cell therapy, which bioengineers a patient’s own immune cells to hunt down and eliminate cancer cells. The custom-designed cells then remain in a patient’s circulation to guard against the cancer’s resurgence. Today, Emily has been cancer-free for more than two years. She is active in school and loves playing with her dog, Lucy.

Emily has appeared prominently in many news stories since her doctors announced dramatic findings during a December 2012 scientific meeting. Shortly after the Precision Medicine Initiative was announced, Emily’s story was even highlighted in a White House blog post about Americans whose lives have been changed by precision medicine.

“If you didn’t know what happened to her, and you saw her now, you would have no idea what she has been through,” said Emily’s mother Kari Whitehead in the White House post.

And just last month, CHOP researchers and colleagues announced continuing promising results. In 39 children with ALL treated with T cell therapy in ongoing clinical trials, 36 had no evidence of cancer one month after treatment. The Food and Drug Administration has officially designated this approach as a Breakthrough Therapy, helping to expedite its progress into broader clinical trials.

“As a world leader in precision medicine, The Children’s Hospital of Philadelphia has made significant investment in its Center for Applied Genomics with the goal of diagnosing and curing pediatric disorders,” Dr. Altschuler noted. “We have already made strides harnessing this technology to better understand and treat cancer, autism, asthma, diabetes and many other childhood illnesses. Emily Whitehead’s personal story is a testament to the real impact this groundbreaking research can make in saving lives.”

To learn more about T Cell therapy at CHOP, see the Hospital’s website.

Permanent link to this article: http://www.research.chop.edu/blog/chop-invited-president-obamas-precision-medicine-announcement/

Feb 02 2015

Research Collaborative Aims to Advance Understanding of Preterm Birth

preterm birth

One in nine babies in the U.S. is born prematurely, according to the March of Dimes.

What causes preterm birth and how to prevent it remains a perplexing riddle in medical science. One in nine babies in the U.S. is born prematurely, according to the March of Dimes, and this rate has barely budged despite years of investigation.

Finding the solutions will require the ingenuity of researchers and physicians at The Children’s Hospital of Philadelphia who are part of a transdisciplinary team established by the new March of Dimes Prematurity Research Center at the Perelman School of Medicine at the University of Pennsylvania. They will apply sophisticated technology and methodology in molecular biology and genomics to help better understand the basis for preterm birth and eventually diminish the leading cause of newborn death in the U.S.

Babies born before 37 weeks are considered to be premature, and because their bodies and organ systems have not matured completely, they often need help breathing, eating, fighting infection, and staying warm. They can have long-term health problems, including cerebral palsy, cognitive impairments, and sensory disorders.

The March of Dimes announced in November that it will invest $10 million over the next five years to create the Prematurity Research Center, which is one of four launched by the foundation since 2011. The new center involves more than 40 investigators who will focus on three research themes that aim to generate important new discoveries regarding preterm birth: bioenergetics and genetics, cervical remodeling, and placental dysfunction.

“This kind of cooperation and collaboration is on a different scale than has ever been developed for preterm birth,” said Rebecca A. Simmons, MD, the project leader for the bioenergetics and genetics theme and an attending neonatologist at CHOP and the Hospital of the University of Pennsylvania. “It’s not only collaborative across our campus and many different departments within the Penn/CHOP system, but we also collaborate between centers, which is a very unique structure.”

The other transdisciplinary prematurity research centers include Stanford University School of Medicine in California; a partnership of Ohio research centers in Cincinnati, Columbus, and Cleveland; and Washington University in St. Louis.

At CHOP, the March of Dimes is particularly interested in researchers’ expertise in mitochondrial biology and biochemistry. Mitochondria are organelles often described as the body’s cellular power plants because they systematically extract energy from nutrient molecules (substrates) that is necessary to perform cells’ most basic and critical functions. Along with Marni Falk, MD, director of the Mitochondrial-Genetic Disease Clinic at CHOP, and Neal Sondheimer, MD, PhD, an attending physician at CHOP, Dr. Simmons will investigate how impaired cellular metabolism could result in power shortages in the reproductive tract that contribute to preterm labor.

“Reproductive tissues — the placenta, the uterus, the cervix — require a huge among of energy,” Dr. Simmons said. “But if for some reason the mitochondria aren’t able to utilize substrates normally, those reproductive tissues may not function properly.”

The study team will look at reproductive tissues from mice and humans with preterm birth to identify any patterns of mitochondrial dysfunction and then see if these disturbances interfere with the tissues’ ability to maintain bioenergetics and metabolic stability during pregnancy.

The Prematurity Research Center’s second theme ties into this hypothesis by exploring how the microbiome may influence cervical remodeling, which is a dynamic process during delivery that transforms the cervix from a rigid structure into a pliable passageway for a baby. The microbiome is a community of bacteria that normally inhabit the vagina and cervix. Preliminary studies suggest that the microbiome is different in women who experience preterm birth. The researchers will explore if abnormal bacteria cause mitochondrial distress and inflammation that accelerates cervical remodeling.

Michal Elovitz, MD, associate professor of Obstetrics and Gynecology and director of the Maternal and Child Health Research Program at the University of Pennsylvania, will lead the theme two projects. Samuel Parry, MD, associate professor of Obstetrics and Gynecology and chief of the Division of Maternal-Fetal Medicine at the University of Pennsylvania, is the project leader for theme three, which also will focus on mitochondrial deficiencies and an unhealthy microbiome as possible factors that disrupt metabolic processes in the placenta and lead to early labor.

“If we do find changes in the microbiome, those are targets for therapeutics that can be developed,” Dr. Simmons said. “We’ll look for strategies to either change the composition of the microbiome or change how the microbiome is functioning.”

Some of the answers to the medical mystery of preterm birth also may lie within complex gene-environment interactions that new research approaches could help to unravel. The study teams will explore the evolving field of epigenetics, which is the study of mechanisms that change how genes are expressed without altering the underlying DNA sequence.

They expect to gain insights into the multiple pregnancy-related risk factors — biological, behavioral, social, physical, and environmental — that could cause epigenetic modifications. For example, Dr. Simmons will explore in theme one how any abnormalities in the genes and biochemical pathways that regulate mitochondrial metabolic function could have a role in preterm birth.

“We think that if we can identify novel metabolic pathways, we can certainly design future interventions,” Dr. Simmons said.

As the Prematurity Research Center moves from the discovery phase to targeting and developing therapeutics, the researchers hope that their findings along the way will spark additional preterm birth studies. The Center will offer a series of pilot grants to investigators to encourage them to tackle this important health challenge. Dr. Simmons expects the first request for grant proposals to be issued in February.

Deborah A. Driscoll, MD, the Luigi Mastroianni Jr. Professor and Chair of the Department of Obstetrics and Gynecology at the Perelman School of Medicine at the University of Pennsylvania, is the director of the Prematurity Research Center, and Dr. Simmons, the Hallam Hurt Professor of Pediatrics, and Dr. Parry are the principal investigators.

Permanent link to this article: http://www.research.chop.edu/blog/research-collaborative-aims-advance-understanding-preterm-birth/

Jan 30 2015

Bridging the Gap Between Womb and World

preterm babiesIn 2012 more than 10 percent of births in the United States were preterm, and nearly 1 percent of births were critically preterm (younger than 26 weeks). These numbers point to a sobering truth: every year, hundreds of thousands of babies are born before they’re ready, requiring urgent medical care immediately after (and likely during) birth.

Coming into the world too early can lead to myriad health issues. Preterm babies, particularly those born before 28 weeks, face a host of challenges, including the fight just to survive.

And preterm babies don’t just face health challenges in the hours and days following their births — many are confronted with obstacles throughout their lives. Those infants who do survive may experience temperature fluctuations, respiratory issues, gastrointestinal and cardiovascular problems, and neurological problems like abnormal blood vessel development, or damage and scarring of blood vessels in the retina.

But investigators at The Children’s Hospital of Philadelphia are on the cusp of an innovative approach to caring for these most delicate infants, one that could radically transform the way they are treated and significantly improve their outcomes.

Alan W. Flake, MD, an attending surgeon, director of the Hospital’s Center for Fetal Diagnosis and Treatment, and Professor of Surgery, Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, has been leading a groundbreaking project on the development of an extracorporeal support of the premature infant (ESPI) system.

Far more than a standard incubator or isolette, the device Dr. Flake’s team has been developing is exactly what it sounds like: an external uterus designed to help preterm infants bridge the gap between their mother’s womb and the world.

“This is an enormously promising study,” said Dr. Flake. “Our system is designed, as much as possible, to avoid the deleterious effects of preterm birth.”

Read more about this exciting program in the Research Annual Report.

Permanent link to this article: http://www.research.chop.edu/blog/bridging-gap-womb-world/

Jan 28 2015

Lessons Learned From OB Unit Closures: Planning, Communication Needed

OB unitHospital staff of obstetric (OB) units are dedicated to ensuring that an infant’s birth is a moment of wonder and joy, but after a series of hospitals in Philadelphia began closing their maternity programs, the OB units that remained open were strained by surges in patient volume, low workforce morale, and lack of care continuity, according to a new study led by researchers at The Children’s Hospital of Philadelphia.

From 1997 to 2012, 13 out of 19 hospital maternity units shut down within the city. The researchers conducted semistructured interviews with 23 obstetric department chairs, leaders of private obstetric groups, obstetricians, nurses, nurse managers, and midwives at 11 hospitals that continued their maternity units. Based on their responses, the researchers learned that better transition planning is needed to help reduce stress on the health systems’ staff and avoid fragmented care for mothers and babies.

“While the degree of obstetric unit closures was larger in Philadelphia than in any other metropolitan area, analyzing the situation may provide useful lessons for other areas as hospital consolidations, closures, and mergers have accelerated since the enactment of the Affordable Care Act,” said study leader Scott A. Lorch, MD, MSCE, a neonatologist and researcher in the Center for Outcomes Research at CHOP.

Dramatic surges in delivery volume were the greatest challenge, according to study participants. Maternity units averaged a 58 percent increase in volume, resulting in frequent overcrowding, understaffing, and lower staff morale. Moreover, the overall patient mix shifted toward poorer patients who were more likely to receive late or no prenatal care.

Prior to the closures, patients often received prenatal care at the same hospital where they gave birth. As the maternity units shut down, the patients had to choose another birthing hospital. Their prenatal health information did not always follow them to the new hospital.

“One clear message from this study is that women need help from their healthcare system in obtaining better continuity of care throughout their pregnancies,” Lorch said.

Overall, the study participants identified two main areas for improvement: better communication among hospitals before closures occurred, and the development of regional solutions to exchange health information and coordinate prenatal care with care at delivery.

“Because hospitals compete with each other for patients, local health departments may need to exercise foresight and planning, identifying hospital units at risk for closing,” Lorch said. “Easing the transition when obstetric units close should improve the experience of both patients and caregivers.”

Lorch and colleagues published their research in the December 2014 issue of Health Affairs and spoke Dec. 8 at a forum sponsored by the journal at the National Press Club in Washington. Co-authors included Ashley Martin, MPH, and Richa Randa, MPH, both from the Center for Outcomes Research at CHOP; and Sindhu K. Srinivas, MD, MSCE, and David Grande, MD, both from Penn Medicine. The study was funded by the Agency for Healthcare Research and Quality, part of the National Institutes of Health.

Permanent link to this article: http://www.research.chop.edu/blog/lessons-learned-ob-unit-closures-planning-communication-needed/

Jan 26 2015

Jeffrey H. Silber, MD, PhD Contributes to Resident Hour, Colon Cancer Studies

Jeffrey H. Silber, MD, PhDThe Children’s Hospital of Philadelphia’s Jeffrey H. Silber, MD, PhD, contributed to two recent studies that span the research spectrum. The first, published in The Journal of the American Medical Association (JAMA), investigated changes to the number of hours medical residents can work. The second investigation, of which Dr. Silber was the lead author and which appeared in the Annals of Internal Medicine, was a study of racial disparities in colon cancer survival.

In the JAMA study, Dr. Silber and colleagues found resident duty hour reforms did not result in significantly higher 30-day readmission or mortality rates. And with the Annals of Internal Medicine investigation, the researchers showed racial disparities in colon cancer survival did not decrease over a 14-year period, from 1991 to 2005.

A pediatrician and healthcare economist, since 1997 Dr. Silber has directed CHOP’s Center for Outcomes Research. He has published extensively on the use of multivariate matching in healthcare, and has applied this approach to outcomes research in both pediatric and adult medicine and surgery, disparities research, and cancer research. Dr. Silber is a professor of Pediatrics, Anesthesiology and Critical Care at the University of Pennsylvania Perelman School of Medicine and professor of Health Care Management at The Wharton School.

With the JAMA study, the researchers sought to determine whether 2011 reforms to the number of hours residents could work had affected patient mortality and readmissions. Implemented by the Accreditation Council for Graduate Medical Education (ACGME), the reforms maintained the 2003 maximum of 80 hours a week but reduced residents’ work limit from 30 to 16 consecutive hours for first-year residents, and to 24 hours for more experienced residents.

The investigators performed an observational study of Medicare patient admissions data from July 1, 2009 to June 30, 2012, comprising some 2,790,356 patients with 6,384,273 admissions across 3104 hospitals, and examined a number of medical conditions (such as congestive heart failure and diabetes) and surgical categories. They found “no significant positive or negative associations of duty-hour reforms” with 30-day all-location mortality or 30-day all-cause readmissions.

“There has been a lot of speculation about the effect of the 2011 ACGME duty hour reforms on patient outcomes, so we looked at death and readmission rates at the national level,” said the study’s lead author, the University of Pennsylvania’s Mitesh S. Patel, MD, MBA, MS.

“Some hoped that by shortening intern shifts from 30 hours to 16 hours, less fatigued residents would lead to less medical errors and improved patient outcomes. Yet, others were concerned that shorter shifts would increase patient handoffs and leave less time for education, thereby negatively affecting patient outcomes,” said Dr. Patel. “These results show that in the first year of the reforms, neither was true.”

Presentation to Blame for Colon Cancer Survival Disparities

 The Annals of Internal Medicine study, meanwhile, examined racial disparities in colon cancer survival rates.

Dr. Silber has previously investigated racial disparities in cancer survival. In August of 2013 he published a study in JAMA that showed differences in how breast cancer patients present at diagnosis are more responsible for racial disparities in 5-year survival than treatment disparities.

In the current study, Dr. Silber and colleagues — including the Wharton School of the University of Pennsylvania’s Paul R. Rosenbaum, PhD; and Penn Medicine’s Bruce J. Giantonio, MD — examined Survey, Epidemiology, and End Results (SEER) Medicare data from 1991 to 2005 across 16 sites to determine the extent to which colon cancer disparities result from presentation at diagnosis or treatment.

One of the most common forms of cancer, colon and rectal cancer account for approximately 10 percent of new cancer cases each year worldwide. According to the National Cancer Institute (NCI), five-year survival rates for colon and rectal cancer vary widely depending on how early it is detected. Based on data from 2004 to 2010, 89.8 percent of patients with localized cancer survived five years after being diagnosed, while only 12.9 percent of patients with distant or metastasized cancer survived five years. And during 2014 the NCI estimates 2014 there will be approximately 50,000 deaths from colon and rectal cancer.

Using SEER data, Dr. Silber and colleagues matched 7,677 black patients aged 65 and older with three groups of 7,677 white patients aged 65 and older — who were followed until 2009 — to investigate the roles of demographics, presentation, and treatment in survival. Finding a “persistent disparity,” the researchers’ data showed a 9.9 percent difference in five-year survival between black and white patients when matched for demographics. When matched for presentation the disparity was 4.9 percent, and when matched for treatment it was 4.3 percent.

“In conclusion, more of the racial disparity in colon cancer survival is explained by differences in health at diagnosis (both the state of the cancer and comorbid conditions) than by differences in subsequent treatment,” the authors write. “Our study suggests that the most effective route to reducing the racial survival disparity is to find ways to reduce the disparity in presentation, so fewer black patients present with advanced disease.”

To read more about the JAMA study, see Penn Medicine’s press release. And for more information about the Annals of Internal Medicine paper, see the journal.

Permanent link to this article: http://www.research.chop.edu/blog/chop-expert-contributes-resident-hour-colon-cancer-studies/

Jan 23 2015

Beyond the Bandages, Nurses Treat Trauma


Pediatric nurses play a key role in preventing injury-related post-traumatic stress by providing trauma-informed care.

It’s no surprise that nurses know trauma. With roughly 2.7 million nurses working in the U.S., versus about 900,000 physicians (according to the American Association of Colleges of Nursing and The Henry J. Kaiser Family Foundation, respectively), nurses are on the front line of clinical care. Nurses are very often the first clinical staff patients meet, and do everything from performing triage and physical exams to conducting research.

Indeed, a recent study from CHOP and Penn State Hershey Children’s Hospital published in the Journal of Pediatric Nursing confirms that pediatric trauma nurses are knowledgeable about practicing trauma-informed care, but points to the need for additional nurse training to help families cope after a child’s injury.

When an injury occurs, both the child and family members may experience traumatic stress reactions interfering with a full recovery. Pediatric nurses play a key role in preventing injury-related post-traumatic stress by providing trauma-informed care, which includes recognizing pre-existing trauma, addressing stress associated with the traumatic event, minimizing potentially traumatic aspects of treatment, and identifying children who need additional monitoring or referrals for more help.

Researchers surveyed nurses across five trauma centers about their knowledge, opinions, and current practices in addressing psychological recovery in their injured patients. More than 90 percent of the nurses surveyed recognize the importance of attending to psychosocial needs as part of trauma nursing care, and 75 to 80 percent report that they encourage parents to turn to family and friends for support and help parents manage a child’s pain and anxiety during procedures. However, fewer nurses surveyed reported directly assessing a child or parent’s distress or providing specific instruction in how to cope with difficult or painful experiences.

“When a child is hospitalized for an injury, nurses play a key role not only in medical care, but also in helping families cope and fully recover emotionally,” said Nancy Kassam-Adams, PhD, director of CHOP’s Center for Pediatric Traumatic Stress. “Taken together with other recent studies that found only one in five trauma centers routinely screen child and youth for traumatic stress responses, these results help to identify gaps in current practice and point to possible policy and training needs.”

The results of this survey suggest that efforts to improve trauma-informed pediatric nursing care should highlight specific skills related to helping patients and their parents manage emotional responses to difficult medical experiences.

In a blog post about the study published on the Center for Research and Injury’s blog, CHOP nurse Christie Alminde, RN, CPN notes nurses’ skills and experiences are “well suited to provide excellent trauma-informed care.”

“When we incorporate an understanding of traumatic stress into our routine interactions with children and families, we can provide trauma-informed nursing care that not only reduces the impact of difficult or frightening medical events for our pediatric patients, but also helps with their emotional reactions to illness and injury,” writes Alminde.

For more information and resources about medical traumatic stress, see the Center for Pediatric Trauma Stress. And to learn more about this study, see the full press release.

Permanent link to this article: http://www.research.chop.edu/blog/beyond-bandages-nurses-treat-trauma/

Jan 21 2015

$50 Million Gift to Fund Research Transformation at CHOP

Raymond G. Perelman.

CHOP will establish the Raymond G. Perelman Campus, an eight-acre area that will serve as a hub of pediatric research and clinical innovation at CHOP.

The Children’s Hospital of Philadelphia (CHOP) today announced a $50 million gift from Raymond G. Perelman. This gift, equal to the largest ever received by CHOP, will directly support a wide range of pediatric research, tackling the toughest and most challenging pediatric illnesses and establishing CHOP as a global center for innovative pediatric study.

In recognition of this extraordinary gift for research, CHOP will establish the Raymond G. Perelman Campus, an eight-acre area that will serve as a hub of pediatric research and clinical innovation at CHOP.

“The significant research funding associated with this gift underscores the commitment of Raymond Perelman to world-class pediatric research and medicine,” said Mortimer J. Buckley, chair, Board of Trustees at The Children’s Hospital of Philadelphia. “Through his generosity, Mr. Perelman is first and foremost improving the lives of children for generations to come and we will always be grateful for his altruism,” he said.

Raymond G. PerelmanBorn in Philadelphia, Raymond G. Perelman was raised in the Feltonville and Olney sections of the city and attended the University of Pennsylvania. After serving in WWII, he began a 50-year career with American Paper Products Co., and is currently CEO of RGP Holdings. Mr. Perelman has served on many Boards of Directors, and has been active in numerous civic organizations, including the Philadelphia Museum of Art, Penn Medicine, and the Albert Einstein Health Center.

“We know first-hand the tremendous resource that CHOP represents to families in the Philadelphia region, across the country and around the world,” said Raymond G. Perelman. “This gift will help to ensure that critically important pediatric research, conducted on this campus, remains second to none; in addition to making a tangible difference in the lives of children around the globe for many years to come, it is my hope and expectation that advances in medical research funded by this gift will benefit us all,” he said.

The gift also establishes the “Raymond G. Perelman Research Fund,” that will provide direct support for:

  • Raymond G. Perelman Center for Cellular & Molecular Therapeutics, designed to re-engineer the body’s immune system to fight, and defeat, cancer, metabolic diseases and other catastrophic illnesses through the efforts of the world’s leading experts in immunotherapy and molecular therapy.
  • Perelman Scholars, two new tenure-track faculty positions at CHOP to be filled by candidates from among the world’s finest pediatric researchers.
  • Perelman Fund for Research Innovation, a permanent source of reliable funding for the CHOP Research Institute to strategically identify and support new pilot research initiatives.
  • Perelman Endowed Chair in Pediatric Ophthalmology to support a highly skilled researcher and physician-scientist seeking to break new ground and forge novel paths critical to understanding and treating ophthalmologic diseases in children.
  • Research Support for general research activities of the CHOP Research Institute.

The newly named Raymond G. Perelman Campus comprises an eight-acre portion of the CHOP site located on Civic Center Boulevard just south of the main hospital and encompasses its most state-of-the-art research and clinical centers, including the Ruth and Tristram Colket, Jr. Translational Research Building, which opened in 2009; the new Buerger Center for Advanced Pediatric Care, under construction and slated to open this summer; and a 2.6-acre landscaped plaza.

To learn more about this extraordinary gift, see the full press release.

Permanent link to this article: http://www.research.chop.edu/blog/50-million-gift-fund-research-transformation-chop/

Jan 20 2015

Office Visits May Be Too Short to Detect Autism Risk

autismIdentifying autism spectrum disorder (ASD) risk early is imperative, because the earlier autism is detected the earlier clinicians will be able to intervene. In general, the younger the patient, the more effective ASD interventions are. However, according to a new study published in Pediatrics, short observations — such as an office visit — may be insufficient when it comes to assessing autism risk.

Led by the Center for Autism Research’s Judith S. Miller PhD, MS, the researchers studied a group of children aged 15 to 33 months with autism, speech delays, and typical development. The researchers asked licensed psychologists with autism expertise — who were unaware of the study participants’ status — to analyze two 10-minute video samples of the participants’ autism evaluations. The experts measured five behaviors, including responding, initiating, vocalizing, play, and response to name.

The article’s first author was Terisa Gabrielsen, PhD, NCSP, of Brigham Young University (BYU). Before moving to BYU, Dr. Gabrielsen completed training at CHOP, where she and Dr. Miller conducted research that informed the current study. That work, also published in Pediatrics, examined the feasibility of a formal autism screening process.

In the current study, the researchers found the experts missed referrals for 39 percent of the children in the autism group. Detecting autism risk based on the brief observations alone was challenging because the children who had autism showed more typical behavior (89 percent of the time) than atypical behavior (11 percent) during that short window.

“It’s not often the pediatrician’s fault that referrals are missed,” Dr. Gabrielsen said. “Even autism experts missed a high percentage of referrals within that short timeframe. Decisions for referral need to be based on more information, including autism screening and information from parents.”

In March of 2014, the Centers for Disease Control and Prevention announced that one in 68 children in the U.S. has an ASD — a 29 percent increase over the 2012 rate. The seemingly growing prevalence of ASD demonstrates the need for accurate autism referral decisions. This decision-making process should include parent observations, developmental testing, a detailed history, and autism screening tools in addition to clinical judgment, the research team concluded.

“Certainly, some young children with autism are clearly impaired and easy to recognize,” noted Dr. Miller in a press release put out by BYU. “However, this study looked at the entire range of children who present to the pediatrician’s office, and we found that many children’s impairments are not immediately obvious. For these children, formalized screening instruments and more time with a specialist may be critical.”

For more information about autism and autism research, see the Center for Autism Research. A description of diagnostic tests and other information on how parents can spot the developmental delays associated with ASD is available in the diagnosis section of Autism Roadmap. The Roadmap provides directories of service providers, community resources, government programs, ideas for various stages of childhood and beyond, and explanations of the latest research on ASD treatments and interventions.

Permanent link to this article: http://www.research.chop.edu/blog/office-visits-may-short-detect-autism-risk/

Jan 16 2015

Translational Research Project Explores Enzymes’ Cancer Role

enzymeWith support from the National Cancer Institute, The Children’s Hospital of Philadelphia Matthew D. Weitzman, PhD, is studying the relation of a family of proteins to cancer. The proteins in question, the ponderously named APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) family of deaminases, play a key role in defending against viruses, but are also being investigated as a possible cause of cellular DNA damage that can lead to cancer.

Dr. Weitzman has been working closely with Abby Green, MD, currently an instructor in Pediatric Oncology. In July of 2014 Dr. Green received a grant of her own to study APOBECs — a two-year Young Investigator Award from Alex’s Lemonade Stand Foundation (ALSF).

Drs. Weitzman and Green’s work seeks to understand better how these enzymes disrupt the genome and cause mutations, and how APOBECs (pronounced AE-POE-BECK) are regulated. Their broad goal is to discover and develop new treatment methods based on a deeper understanding of the relationship between these enzymes and cancer cells. For her part, Dr. Green’s ALSF grant funds an investigation into whether the DNA mutations caused by APOBECs make cancer cells more receptive to drugs.

The work builds on recent investigations into the enzymes’ relation to cancer by Dr. Weitzman and others. In 2011 he published a paper in EMBO Reports with colleagues from the Salk Institute showing that some APOBECs could cause genomic instability. His five-year R01 grant from the National Cancer Institute seeks to build on the EMBO Reports work.

“The grant is asking basically can we show that these enzymes actually cause those [mutational] signatures and fulfill what is predicted retrospectively,” Dr. Weitzman said. “The next questions address what regulates activity, what makes sure it doesn’t happen normally, what are the modifications, what are the interactive proteins, where’s it expressed and localized in the cell, and other fundamental questions about these potentially harmful enzymes.”

Potentially Paradoxical Proteins

 Though APOBECs have been the focus of increased attention in recent years, they remain poorly understood. How, some have wondered, could enzymes that perform an immune function also induce cancer-causing mutations? A review of these enzymes offered a possible answer: age. In their Intrinsic Immunity, Current Topics in Microbiology, the University of Minnesota’s Reuben S. Harris, PhD, and Eric W. Refsland, PhD, address the question of how, and why, enzymes whose primary role is to fight viruses could be a cause of human cancer.

“An attractive explanation for this apparent conundrum may be that [APOBECs’] innate function is important early in life and for the health of the species, for instance, in germ cells or early development, whereas the toll of cancer is not imposed in most instances until after the reproductive years,” they note. “In any event, much more work is now justified on APOBEC3B and its role in breast and, potentially, other human cancers.”

Hence the importance of studies like Drs. Weitzman and Green’s. Dr. Weitzman pointed out that while cancer genome sequencing studies have revealed a great deal of information about how cancer arises, and discovered genes associated with certain cancers, they don’t necessarily provide the mechanism by which things happen.

“We want to bridge that gap,” said Dr. Green.

And though their study is mechanistic, greater knowledge of APOBECs’ role in causing cancer, and how this family of enzymes is regulated, could lead to diagnostic and therapeutic approaches in the future. “If we find that these APOBECs are involved in pediatric cancers, there may be a diagnostic role, or a therapeutic opportunity. We have lots of translational ideas, but we just have to get this first work done,” Dr. Green added.

Indeed, it is CHOP’s unique ability to pair laboratory researchers with clinicians like Dr. Green that allows investigators to think more translationally, Dr. Weitzman noted. He said that his work has really benefitted from the input and expertise of Dr. Green, who is the first clinician to work in his lab.

“CHOP has this ability to pair basic researchers with clinicians, and both sides stimulate each other to think together about translational ideas,” Dr. Weitzman said.

Permanent link to this article: http://www.research.chop.edu/blog/translational-research-project-explores-enzymes-cancer-role/

Jan 14 2015

Researchers Receive Grant to Study TMJ Biology, Long-term Maintenance

TMJOf all the joints in the body, perhaps the most unique, complex, and understudied is the temporomandibular joint (TMJ). The TMJ, which is located close to the ears, is a bilateral movable articulation, connecting the lower jaw (mandible) to the bone at the side of the skull (temporal bone). Its structure include a distinctive feature called an articular disc that acts as a shock absorber and reduces friction so that the bony parts of the joint can glide smoothly, allowing us to chew, talk, yawn, and open our mouths wide to say “Ahhh.”

Researchers at The Children’s Hospital of Philadelphia, Eiki Koyama, DDS, PhD, a faculty member in the Division of Orthopedics, and Hyun-Duck Nah, DMD, PhD, an orthodontist in the Division of Plastic and Reconstructive Surgery who works with patients who have craniofacial deformities, recently received a grant from the National Institute of Dental & Craniofacial Research to study the development of the TMJ, the mechanisms that maintain it, and how these processes may be altered in disease. They aim to use this knowledge to inform future therapeutic strategies in pediatric and adult medicine.

The TMJ begins to form within the first few months after conception, experiences active growth during childhood and adolescence, and then undergoes adaptive remodeling throughout life. The exact prevalence of TMJ disorders in the general pediatric population is uncertain, but guidelines from the American Academy of Pediatric Dentistry cite that upwards of 25 percent of children ages 5 to 17 have some symptoms of TMJ disease, and 1 percent to 2 percent are in need of treatment.

Pediatric TMJ disorders can be congenital or acquired, such as craniofacial abnormalities, juvenile rheumatoid arthritis, and injuries or infection that damage the joint. Symptoms and signs of TMJ disorders vary depending on etiology and severity, but commonly include difficulty opening the mouth, locking of the joint, difficulty with mastication and nutrition, and facial and jaw muscle pain. Furthermore, defective TMJ function often results in under-development of the mandible and abnormal facial growth.

In previous research, Dr. Koyama’s group demonstrated that mice with deletion of a specific gene, Indian hedgehog (Ihh), failed to form a normal TMJ. The joint lacked integral components including its distinctive articular disc, joint cavities, and the specialized cell layers that produce lubricin. Lubricin is a lubricant that protects the TMJ from frictional loads and thus is essential for long-term maintenance of joint integrity.

In the current study, the Koyama and Nah team now plan to further define the roles of Ihh and additionally to delineate the role of two genetic pathways, TGF-β1 and PTHrP, that they suggest Ihh uses to orchestrate TMJ formation, function, and lubricin production. They predict that deterioration of joint lubrication with age or by other insults may underlie disc adhesion and degenerative TMJ disorders, which are prevalent in the adult population.

While this research is still at the basic science stage, Dr. Nah, who is also a research associate professor of surgery at the Perelman School of Medicine at the University of Pennsylvania, said that the ultimate goals of the study include translation of findings to recreate a functional TMJ for those patients with missing or defective TMJs.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-receive-grant-study-tmj-biology-long-term-maintenance/

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