Scientists at Children’s Hospital of Philadelphia revealed a surprising way that adenovirus uses a viral protein to prevent infected cells from releasing a danger signal from the nucleus to alarm the immune system.

Why it matters: The novel mechanism the researchers discovered that enables this common human virus to evade the immune system establishes new connections within the fields of virology, immune signaling, and chromatin biology. Knowledge of these molecular interactions could lead to new strategies to control unwanted inflammation in other diseases such as cancer and severe infections such as sepsis.

Key CHOP investigators: Daphne C. Avgousti, PhD, CHOP postdoctoral fellow; Matthew Weitzman, PhD, CHOP virologist and associate professor of Pathology, Pediatrics and Microbiology at the Perelman School of Medicine at the University of Pennsylvania; G. Scott Worthen, MD, CHOP neonatology researcher and professor of Pediatrics at Penn.

How they did it: Since the adenovirus protein known as protein VII has a role on the compacted viral genome, the study group applied research techniques and principles that are typically used to study histones, the proteins that condense a cell’s DNA into chromatin (the collection of chromosomes). They tested whether protein VII could mimic histones and disrupt the structure of cellular chromatin in cell culture, in human lung tissue in the laboratory, and in mouse models — and found that it did. They also found that this viral protein actually retains the molecule HGMB1, an important danger signal, within the nucleus, and as a result suppresses the recruitment of immune cells.

Quick thoughts: “We have learned a new way that this virus evades the immune system, and this insight suggests a potential method of exploiting the process to control immune responses for patient benefit,” Dr. Weitzman said.

Next steps: The scientists will continue to investigate other viral proteins to determine whether they act similarly, in hiding alarm signals from the immune system.

Where it was published: Nature

Funding sources: The National Institutes of Health supported this study (grants CA115299, GM112414, and CA097093, and others).

Read more: See the Cornerstone blog post.

The largest genetic study to date of childhood body mass index (BMI) identified 15 gene locations associated with childhood BMI, three of which were novel.

Why it matters: The genetics of childhood BMI has remained largely unknown. The crucial novel insight into the biology of obesity this study provides may also lead to opportunities for generalized therapeutic intervention.

Key CHOP investigators: Struan F.A. Grant, PhD, CHOP genomics researcher and associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania; Jonathan Bradfield, CHOP bioinformatics specialist.

How they did it: The researchers performed a meta-analysis that covered 33 genome-wide association studies, including a total of more than 45,000 children, all of European ancestry. Of that total, there were 35,668 children from 20 studies in the discovery phase, and 11,873 children from 13 replication studies. In all, they found that 15 risk-susceptibility loci account for 2 percent of the variance in childhood BMI.

Quick thoughts: “As we continue to identify gene variants implicated in pediatric obesity and body mass, we are laying a foundation for research that could provide useful biological targets for better treating childhood obesity, and its negative health consequences,” Dr. Grant said.

Next steps: Further research may determine whether the three novel loci the study group discovered influence BMI only in childhood, or whether their effects are stronger during childhood.

Where it was published: Human Molecular Genetics

Funding sources: The National Institutes of Health (grant HD056465) and the Cotswold Foundation funded CHOP's involvement in this study.

Read more: See the CHOP press release.

Researchers from CHOP suggest that the U.S. may be underestimating the incidence of pediatric concussions because those counts currently are based solely on emergency department (ED) visits or organized high school and college athletics data.

Why it matters: The investigators provided a better estimate of the scope of the problem by examining concussion visits across an entire pediatric health care network, which will allow clinicians to more effectively prevent and treat concussions. In particular, the findings demonstrate that the primary care setting is an integral part of concussion care management.

Key CHOP investigators: Kristy Arbogast, PhD, co-scientific director of CHOP’s Center for Injury Research and Prevention and research associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania; Christina Master, MD, CHOP pediatric sports medicine specialist and associate professor of Clinical Pediatrics at Penn.

How they did it: Using the CHOP electronic health record, the study team retrospectively analyzed more than 8,000 concussion diagnoses over a four-year period (July 2010 – June 2014), among children up to 17 years who received their primary care within the CHOP regional pediatric network. During that period, primary care visits as the point of entry increased 13 percent, with a corresponding 16 percent decrease in point-of-entry ED visits. Among the study participants, 82 percent had their first concussion visit with a primary care pediatrician, 12 percent went to the ED, 5 percent first saw a specialist (sports medicine, neurology, trauma), and 1 percent were admitted directly to the hospital.

Quick thoughts: “We learned two really important things about pediatric concussion healthcare practices,” Dr. Arbogast said. “First, four in five of this diverse group of children were diagnosed at a primary care practice — not the emergency department. Second, one-third were under age 12, and therefore represent an important part of the concussion population that is missed by existing surveillance systems that focus on high school athletes.”

Next steps: Researchers will continue to explore the large and diverse electronic health record at CHOP to answer many questions about the natural history of pediatric concussion and apply this knowledge to many other clinical effectiveness issues.

Where it was published: JAMA Pediatrics

Funding sources: The U.S. Centers for Disease Control and Prevention funded this research.

Read more: See the CHOP press release, and check out the infographic.

Adherence to a well-visit schedule is a priority for preterm infants because they are at increased risk for medical complications and lifelong health problems. That is why this study’s findings were disconcerting to researchers at CHOP: Only 43 percent of preterm infants received all expected health supervision visits during the first 18 months of life.

Why it matters: Missing well visits can make a substantial difference in health outcomes for premature infants, according to this retrospective study. In addition to not getting vaccinations, the babies were less likely to receive screening tests and developmental assessments on time.

Key CHOP investigator: Scott Lorch, MD, MSCE, an attending neonatologist at CHOP and an associate professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania

How they did it: The study team looked at outpatient data from a retrospective cohort of 1,854 preterm infants born between 2005 and 2009 who received care at CHOP’s primary care network. Upon analyzing the data, the researchers identified two primary reasons why families missed the well visits. Sometimes they showed up for a well visit, but baby was not feeling well that day, so it became a sick visit. Other times they came in for a sick visit and then cancelled their next well visit. In both scenarios, the well visits were never rescheduled, and families did not receive the preventive care that normally would have occurred during those sessions.

Quick thoughts: “This is one of the first studies to provide documented evidence that there are health consequences for missing well visits,” Dr. Lorch said. “It shows how difficult it is for providers to get caught up with the services that these visits provide to patients.”

Next steps: In future research, Dr. Lorch and his study team will take a closer look at some of the potential barriers to families’ attendance at well visits. They also will investigate factors that could improve continuity of care and determine ways to avoid delays in immunizations and help close gaps in health monitoring.

Where it was published: Pediatrics

Funding sources: National Institutes of Health grant R01 HD057168 supported this study.

Read more: See the Cornerstone blog post

Researchers at CHOP describe how two small adapter proteins, Ndfip1 and Ndfip2, contribute to the braking system that keeps T cells from instigating hyperactivity of the immune system and producing proinflammatory cytokines that are involved in ramping up inflammation.

Why it matters: T cells are the immune system’s watchdog to recognize serious threats. But sometimes T cells can be too zealous and set in motion a signaling cascade that can cause allergic reactions to everyday things and even attack your body’s healthy cells by mistake. CHOP scientists learned more about what is occurring at a basic cellular level to drive inappropriate immune cell responses.

Key CHOP investigators: Claire O’Leary, PhD, then a postdoctoral fellow at CHOP and Paula Oliver, PhD, an investigator in the Cell Pathology Division

How they did it: The researchers discovered how this molecular braking system works in two distinct stages. Ndfip1 comes on early when the immune system perceives a substance as being foreign or dangerous, and its expression skyrockets as T cells are stimulated. When the T cells are re-exposed to the antigen and stimulated a second time, they initiate a more aggressive and rapid memory response that requires both Ndfip1 and Ndfip2 to be activated in order prevent an overly exuberant immune response. They also found that when Ndfip1 and Ndfip2 were not functioning, it halted degradation of a protein called Jak1, which is essential for signaling via certain types of cytokine receptors. Without appropriate down regulation of Jak1, expansion and survival of pathogenic effector T cells increased. The study authors suggest that Ndfip1 and Ndfip2 work together to regulate the cross talk between the T cell receptor and cytokine signaling pathways to prevent inappropriate T cell responses.

Quick thoughts: “We think of these proteins as being negative regulators of inappropriate activation,” Dr. O’Leary said. “In the absence of these proteins, the cells are accelerating immune reactions without a lot of guidance. They become self-directed and differentiate toward a path that is highly proliferative. They produce a lot of Th2 type cytokines associated with allergic disease.”

Next steps: As scientists learn more about the basic mechanisms of T cells’ negative regulatory pathways, these findings could point the way to future drug therapies.

Where it was published: Nature Communications

Funding sources: Funding for this work came from the American Asthma Foundation and the National Institute of Allergy and Infectious Disease.

Read more: See the Cornerstone blog post.

A team of researchers from the Pediatric Cardiac Genomics Consortium studying the role of genetics in congenital heart disease (CHD) confirmed their longstanding suspicion: Some of the same gene defects underlie certain cases of congenital heart malformations and neurodevelopmental disorders.

Why it matters: CHD is the most common type of birth defect in the U.S. and one of the leading causes of infant death. These findings may allow researchers to tailor future treatments to children based on their personal genetic risk for neurodevelopmental disorders. Clinicians may be able to intervene earlier on, when the brain is still developing, which could improve developmental outcomes for children with CHD.

Key CHOP investigator: Elizabeth Goldmuntz, MD, FAAP, FACC, a cardiologist at CHOP, and professor at the Perelman School of Medicine at the University of Pennsylvania

How they did it: Researchers sequenced the whole exome, or expressed part of the genome, from 1,213 family trios (a child with CHD and the mother and father), to identify spontaneously arising (de novo) mutations in the child’s genes that did not come from either parent. These damaging mutations disproportionately occurred in genes for developmental processes that are highly expressed in the developing heart and brain.

Quick thoughts: “Congenital heart disease is the most frequent serious birth defect, so as we discover more of these gene alterations, we will be better able to provide genetic counseling and refine patient care for many families and children,” Dr. Goldmuntz said.

Next steps: Follow-up research must be done before the findings could be used in early screening tests. Also, further analysis of these mutated genes may help researchers to identify new biological pathways critical to the heart and brain’s development. Ultimately, these pathways might eventually be targeted with specific drugs, but such targeted therapies will require more research.

Where it was published: Science

Funding sources: The National Institutes of Health provided grant support for this study.

Read more: See the Cornerstone blog post.

Scientists at CHOP are beginning to glimpse exactly how a gestating infant’s developing brain forms important connections. Before and during these critical weeks, brain development patterns emphasize early, efficient connectivity within the primary sensorimotor cortex.

Why it matters: The findings help establish a normal reference for how connectivity patterns develop in the brain. The emphasis on developing the primary sensorimotor cortex early prepares a baby to handle the basic needs of sensation and movement after birth.

Key CHOP investigator: Hao Huang, PhD, investigator in radiology at CHOP and research associate professor at the Perelman School of Medicine at the University of Pennsylvania

How they did it: The researchers used resting-state functional magnetic resonance imaging scans to map the functional connectivity in the brains of 40 infants soon after their birth at various preterm ages, from as early as 31 postmenstrual weeks, up to full-term, or 42 postmenstrual weeks. Even the youngest preterm babies’ brains had a characteristic called “small worldness” in their entire brain connectivity, a feature of networks that offer easy navigation from one area to another. But as gestational age increased, so did a quality called rich club structure, characterized by nodes of densely connected regions that make signaling more efficient within areas of the brain.

Quick thoughts: “In certain periods, some brain regions develop at faster rates,” Dr. Huang said. “Although it’s heterogeneous, it’s not random. There is a well controlled, organized pattern at work.”

Next steps: Dr. Huang has subsequently been awarded a new National Institutes of Health (NIH) grant to study infant brain connectivity changes from ages one month to two years, and to establish a quantitative Penn-CHOP infant brain image atlas. Ultimately, he hopes to identify infant brain biomarkers of atypical connectivity that may occur in various conditions, ranging from autism spectrum disorder to cerebral palsy. If these brain indicators can allow earlier identification of these conditions, children could potentially begin early intervention services sooner and grow up with fewer impairments related to their condition. He also plans to study connectivity development from birth through adolescence.

Where it was published: Cerebral Cortex

Funding sources: The NIH (grants R01MH092535, U54HD086984, and R01MH092535-S1), National Science Fund for Distinguished Young Scholars (grant 81225012), the Natural Science Foundation of China (grants 91432115 and 31221003), the 111 Project (grant B07008), and the Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (grant CNLYB1407) supported this study.

Read more: See the Bench to Bedside article.

A team of scientists at CHOP discovered a mechanism by which proteins that are essential for cell division in healthy cells can drive excess growth and proliferation in cancer cells. They found that when there is an excess quantity of a protein called E2f1, which normally activates the expression of various genes for the cell cycle of reproduction, this protein binds to a molecular complex of proteins that unzip adjacent DNA strands and allow other E2f proteins to amplify the activity of many other genes. In particular, some of these other genes regulate a long-known process of rewiring the energy metabolism in cancer cells for rapid growth, known as the Warburg effect.

Why it matters: Scientists have known that E2f1 is overexpressed in the late stages of many pediatric and adult cancers and is linked to poor prognoses, but they did not know why having more of this protein was bad news for cancer patients. Now they have linked a molecular activity of this protein to other known mechanisms of cancer cell growth.

Key CHOP investigator: Patrick Viatour, PharmD, PhD, investigator at CHOP and assistant professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania

How they did it: Most of this work was done in a mouse model of hepatocellular carcinoma, a form of liver cancer primarily affecting adults. In addition, Dr. Viatour and his team performed further experiments using human cell lines from multiple types of pediatric and adult cancers. In just over half of these human cell experiments, they found the same complex of the DNA-unzipping proteins Pontin and Reptin binding with E2f1, suggesting that the same mechanism may occur in many human cancers.

Quick thoughts: “This finding really expands what’s been considered textbook material,” Dr. Viatour said. “We thought E2f was mostly promoting cancer growth through aberrant cell cycle activity. If you only have a little E2f activity, it is just the cell cycle. But if you have a lot of E2f activity, as you have in cancer, it’s way more than that. These factors promote cancer progression by actually activating multiple gene programs.”

Next steps: The team’s next phase of research will seek to better understand this mechanism of amplified gene expression to determine whether it is not only associated with cancer progression, but truly critical to it. If so, Dr. Viatour said, there is potential to pursue cancer treatments that would target the E2f1/Pontin/Reptin complex in cancer cells to stop excessive gene expression before it starts. Targeting protein-protein interactions has been successful in other cancer therapies.

Where it was published: Nature Communications

Funding sources: Dr. Viatour’s funding from the W.W. Smith Charitable Trust Fund, the Stand Up to Cancer, Alex’s Lemonade Stand, and the Canuso Foundations, and start-up funds from the Center for Childhood Cancer Research at CHOP supported this research.

Read more: See the Cornerstone blog post.

New research in laboratory animals at CHOP suggests that the drug Palovarotene may prevent multiple skeletal problems caused by a rare but extremely disabling genetic skeletal disease, and may even be a candidate for use in newborn babies with the condition.

Why it matters: Currently untreatable and painful, Fibrodysplasia Ossificans Progressiva (FOP) often causes death early in adulthood. In this disease, cartilage and bone form and accumulate in muscles and other tissues where they do not belong, starting in early childhood. This pathological process, collectively called heterotopic ossification (HO), causes progressive loss of skeletal motion and hampers skeletal growth, joint function, breathing and swallowing.

Key CHOP investigator: Maurizio Pacifici, PhD, developmental biologist and director of Orthopedic Research in the Division of Orthopedic Surgery at CHOP and a professor of Orthopaedic Surgery at the Perelman School of Medicine at the University of Pennsylvania; Masahiro Iwamoto, DDS, PhD, research associate professor in Orthopaedic Surgery at CHOP and Penn.

How they did it: The extra bone that occurs in FOP appears first as cartilage before becoming fully mature bone cells, and Palovarotene was identified as a drug candidate because it selectively targets a regulatory pathway involved in cartilage formation. The current study extended previous research by Drs. Iwamoto and Pacifici showing that the drug inhibited HO in mouse models of genetic HO and injury-induced HO. In mice carrying the genetic mutation that causes most cases of FOP, the drug had potent effects, preventing HO and preserving limb motion and normal bone growth in young mutant mice. Nursing mouse mothers given the drug were also able to pass on its benefits to their offspring with the mutation.

Quick thoughts: “If these results translate to humans, we may be able to treat children with FOP early in life, before the disease progresses,” Dr. Pacifici said.

Next steps: Clementia Pharmaceuticals is currently conducting phase 2 clinical trials in individuals with FOP. The international study is being done at three sites, including the FOP Center at Penn Medicine, and is testing whether Palovarotene is safe and effective in reducing or preventing HO in children and adults experiencing disease flare-ups.

Where it was published: Journal of Bone and Mineral Research

Funding sources: Funds for the CHOP researchers were from the National Institutes of Health (grants AR056837 and AR41916) and the U.S. Department of the Army (contract W81XWH-07-1-0212). Funds for collaborating scientists at Penn were from the International Fibrodysplasia Ossificans Progressiva Association, the Penn Center for Musculoskeletal Diseases, the Ian Cali Endowment for FOP Research, the Whitney Weldon Endowment for FOP Research, and the Penn Center for Research in FOP and Related Disorders.

Read more: See the CHOP press release.

An international team of oncology researchers led by CHOP and Dana-Farber Cancer Institute has discovered that an abnormal fused gene that drives pediatric brain tumors poses a triple threat, operating simultaneously through three distinct biological mechanisms — the first such example in cancer biology.

Why it matters: This finding potentially offers triple benefits as well — more accurate diagnoses, clues for more effective treatments and new insights into molecular processes underlying other types of cancer.

Key CHOP investigators: Adam Resnick, PhD, neuro-oncology researcher in the Division of Neurosurgery at CHOP and the Department of Neurosurgery at the Perelman School of Medicine  and the co-director of the Center for Data-Driven Discovery in Biomedicine at CHOP; Payal Jain, University of Pennsylvania graduate student.

How they did it: Scientists investigated pediatric low-grade gliomas (PLGGs), a varied group collectively representing the most common pediatric brain tumor. Drawing on multiple consortia and previously uncurated datasets, they analyzed the largest amount of data available for PLGGs, representing the genomes of 249 such tumors. In one class of these tumors (angiocentric gliomas, of which there were 19), virtually all had two genes, MYB and QKI, fused together. They investigated this fused gene and found that it acts in three ways: The rearranged gene expresses truncated, constitutively active fusion proteins that give rise to cancer; the fusion protein is abnormally expressed in brain tissues due to the movement of enhancer regions during the fusion event, and this abnormal expression leads to a feedback loop that drives cell proliferation; and the fusion gene disrupts QKI’s protective role as a tumor suppressor.

Quick thoughts: “The study expands our current understanding of cancer, by focusing attention on the multiple mechanisms occurring simultaneously, and bringing into relief how gene fusions may give rise to epigenomic dysregulation,” Dr. Resnick said. “Gene fusions occur in many other cancers in both children and adults, so our findings may apply more broadly to other cancers.”

Next steps: Identifying the MYB-QKI fusion gene as a defining event in angiocentric glioma may allow oncologists to better diagnose this subtype of tumor, guiding them toward directed therapies less likely to overtreat or undertreat children. Better understanding the mechanisms involved in this gene fusion can lead to treatment strategies targeting any of these mechanisms, including potential drugs that may be effective against the type of epigenomic dysregulation seen in these tumors.

Where it was published: Nature Genetics

Funding sources: CHOP’s collaborative low-grade glioma discovery work is supported by A Kids’ Brain Tumor Cure Foundation/Pediatric Low-Grade Astrocytoma Foundation, Voices Against Brain Cancer, Thea’s Star of Hope, and Why Not Me Inc. Multiple additional grants from the National Institutes of Health and more than 20 foundations also supported this research across partnering institutions.

Read more: See the CHOP press release.

An international study team led by researchers from CHOP’s Center for Applied Genomics focused on 10 autoimmune diseases that begin in childhood and found that they indeed have some shared genetic underpinnings.

Why it matters: Autoimmune diseases occur when they body’s immune system attacks and destroys healthy body tissue by mistake. As much as 7 to 10 percent of the Western Hemisphere’s population is affected. Identifying the biological mechanisms that underlie these disorders, and especially shared pathways, can lead to targeted therapeutic approaches for multiple related diseases.

Key CHOP investigators: Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP and professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania; Yun (Rose) Li, MD, PhD, then a graduate student at the Perelman School of Medicine.

How they did it: Researchers performed a meta-analysis including a case-control study of 6,035 subjects with autoimmune disease and 10,700 controls, all of European ancestry. The research encompassed 10 pediatric autoimmune diseases: type 1 diabetes, celiac disease, juvenile idiopathic arthritis, common variable immunodeficiency disease, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, psoriasis, autoimmune thyroiditis, and ankylosing spondylitis. The investigators found 22 genetic loci that were shared by at least two of the autoimmune diseases, and 19 of these were shared by at least three diseases. The team then studied the pathogenic roles of the shared genes, focusing on how these genes upregulated gene expression in specific cell types and tissues to find patterns that were directly relevant to specific diseases.

Quick thoughts: “Our approach did more than finding genetic associations among a group of diseases,” Dr. Hakonarson said. “We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy.”

Next steps: Identifying specific autoimmune diseases’ genetic architecture gives researchers opportunities to better target potential therapies, including the possibility of repurposing existing drugs available for the treatment of other diseases.

Where it was published: Nature Medicine

Funding sources: The National Institutes of Health, the Wellcome Trust, the Paul and Daisy Soros Fellowship for New Americans, the Crohn’s & Colitis Foundation of America, the Juvenile Diabetes Research Foundation, the Lupus Research Institute, and Institutional Development Funds from CHOP supported this research.

Read more: See the story on the Cornerstone blog.

Mitochondria, the tiny structures inside our cells that generate energy, may also play a previously unrecognized role in mind-body interactions. Researchers led by a pioneer of mitochondrial medicine at CHOP found that relatively mild alterations in mitochondrial genes have large effects on how mammals respond to stressful changes in their environment.

Why it matters: This insight may have broad implications for human psychology and for the biology of psychiatric and neurological diseases, including implications for the hereditary basis of neuropsychiatric diseases and for the role of stress in human health. It lends support to the idea that an important reason for our limited progress in understanding the genetic and biologic basis of psychology is our lack of appreciation for the importance of systematic alterations in energetic metabolism.

Key CHOP investigators: Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

How they did it: Researchers subjected mice to a standardized psychological stress: placing them in restraint for a brief period. They then measured the effects of this stressor on the animals’ neuroendocrine, inflammatory, metabolic, and gene transcription systems. In humans, all of these systems are involved in behavioral responses to stress and long-term susceptibility to stress-related diseases. They found that in the mice, relatively mild mutations in mitochondrial genes produced unique whole-body stress-response signatures, indicated by physiological and gene expression patterns.

Quick thoughts: “Our recent papers strongly suggest that by reorienting our investigations from the anatomy of the brain and brain-specific genes to the mitochondria and the bioenergetics genes, we may have a more productive conceptual framework to understand neuropsychiatric disease,” Dr. Wallace said. “If so, this will spawn a whole new generation of neuropsychiatric therapeutics.”

Next steps: While much more research remains to be done on the role of mitochondria on human behavior, identifying the altered mitochondrial states associated with neuropsychiatric diseases may help suggest new therapies. These may permit physicians to more effectively ameliorate the effects of environmental stressors on human health.

Where it was published: Proceedings of the National Academy of Sciences

Funding sources: The Simon Foundation and the National Institutes of Health (grants NS21328, DK73691, and CA143351) supported this research.

Read more: See the CHOP press release.