News in Brief
Do parents’ religious or spiritual beliefs make them more likely to comply with a child’s treatment regimen?
A new National Institute of Child and Human Development (NICHD) study at Cincinnati Children’s will explore whether and to what extent religion affects compliance. The $590,868 grant will run for five years. It is the first such study to be federally funded in a pediatric setting.
Daniel Grossoehme, DMin, a faculty member in the Division of Pulmonary Medicine and a chaplain serving the Cystic Fibrosis (CF) Center, will lead the study, which will involve approximately 100 families with children under the age of 12 who have CF.
“The treatment regimen that these parents are asked to follow at home each day with their children is extremely burdensome,” says Grossoehme. Care can vary depending on the child’s state of health, but under the best of circumstances, he says it requires at least an hour and a half each day.
Grossoehme points to prior adherence studies that show most children with CF get about half the breathing treatments they should and even less of important enzyme supplements.
“There’s almost nowhere to go but up,” he says. “Anything to improve adherence is a good thing.”
So he wants to explore whether spirituality or religion plays a part. He plans to use a combination of interviews and already-validated quantitative scales to measure religious coping styles.
“Most of the major world religions believe in some version of respect for or sanctification of the body,” he says. “Because it’s part of God’s creation, it’s important to take as good care of it as you can. For some parents, might this contribute to compliance?”
If it does, Grossoehme believes it could open up ways to support spiritually oriented parents in being adherent or could serve as a way to identify families at risk.
Research has shown that religion is a significant factor in parents’ medical decision making, reports Grossoehme, although they don’t typically share this information with their physicians.
He hopes this study will help put some science behind a notion that has been largely anecdotal.
“It is certainly something that seems to be tremendously important to our patients and families. And if it is motivating adherence, we need to know that,” he says. “Some clinicians remain skeptical, but to the extent that our parents and families value it, we need to take this seriously so we can work with them.”
Cincinnati Children’s has been selected to lead a five-year federal project to vastly expand an animal database vital to the study of human embryonic development.
The project will use a $3.7 million grant from the National Institute of Child Health and Human Development to expand Xenbase, a massive collection of data about the frogs Xenopus laevis and Xenopus tropicalis.
For many years, biologists have studied frog embryos to gain insights into the many dramatic changes that occur during earliest phases of life.
“Much of what we understand about the molecular pathways controlling the first trimester of human development comes from animal models, especially frogs, fish and mice,” says Aaron Zorn, PhD, a researcher in the Division of Developmental Biology and principal investigator for the grant. “With the genome sequence complete we have a list of all the genes, but now, in the post-genomic era, we need to figure out what they all do. With the recent acceleration in functional genomics we have so much information coming in that the real challenge is to organize it so that researchers can use it effectively.”
To that end, scientists at the University of Calgary developed Xenbase about five years ago to begin collecting Xenopus biological and genomic data, with support from the National Institutes of Health (NIH). The new grant, awarded in June, vastly expands the scope of Xenbase and reflects a trend of NIH support for building animal model databases. Other examples include ZFIN for zebrafish, WormBase for C.elegans, FlyBase for Drosophila, and MGI (Mouse Genome Informatics).
Xenbase already houses a catalog of Xenopus genes, images of development stages, a library of Xenopus-related research papers and more. However, Zorn and colleagues plan to add much more information about where genes are expressed during development, what precise functions they perform, how they interact with other genes, and whether the homologous genes in humans are associated with disease. Under the new grant, the University of Calgary will continue to develop software. Cincinnati Children’s will assemble a team of data curators who will hunt through tens of thousands of research papers and gene profiles to further build Xenbase.
This information will be open for use by researchers worldwide. Past studies involving Xenopus have shed much light on the mechanisms of embryonic development–including how cells divide, the patterning of the basic body plan, the determination of cell fate, and the early formation of major organ systems. Few can predict what new discoveries will come from researchers quickly accessing the information in Xenbase.
“This is about where the future is headed,” Zorn says.
Researchers have identified a set of “molecular signatures” for biliary atresia–the most common cause of liver transplant in children – that can help identify the progression of disease at diagnosis and predict clinical outcomes. Biliary atresia is a rare disease of the liver and bile ducts that occurs in infants. The disease blocks bile flow from the liver to the gallbladder, which eventually causes liver failure.
In a study published in Genome Medicine, scientists at Cincinnati Children’s found that when using traditional liver biopsy analysis, only 14 of 47 infants with biliary atresia could be identified on the basis of either inflammation or fibrosis (development of excess fibrous connective tissue). By examining the entire genome in the patients’ livers, however, they developed a molecular signature that could identify the vast majority of patients with biliary atresia, and determine if they had either inflamed or fibrotic liver tissue.
“This suggests that the molecular profile at diagnosis may determine the ‘stage’ of liver disease through specific biological pathways,” says Jorge Bezerra, MD, a gastroenterologist at Cincinnati Children’s and senior author of the study. “Infants with inflammation were younger, indicating that inflammation may reflect an earlier stage of disease – particularly given that those with fibrosis had decreased survival without transplant.”
The researchers hope that this new ability to identify how liver disease will progress will allow them to tailor current treatments to the stage of the liver disease, and that the findings will eventually lead to improved treatments.
Scientists have identified a key molecular regulator of cardiac hypertrophy (enlargement of the heart). The discovery could point the way to new treatment options for a disease known to lead to heart failure and early death.
Researchers at Cincinnati Children’s, the University of North Carolina at Chapel Hill, and the Medizinische Hochschule Hannover in Germany identified the protein CIB1 as a key regulator in the production of the enzyme calcineurin, which regulates heart cell growth.
In the study, researchers genetically engineered mice to either produce too much CIB1 or not produce the protein at all. Mice with higher-than-normal levels of CIB1 in their bodies developed cardiac hypertrophy. Mice engineered to lack CIB1, on the other hand, did not develop the condition and showed protection from hypertrophy. Additional study of human and mouse heart tissue confirmed that there was more CIB1 present in subjects with cardiac hypertrophy.
“Hypertrophic heart disease is a leading health problem in Western countries,” says Jeffery Molkentin, PhD, lead investigator, a researcher in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s and a Howard Hughes Medical Institute investigator. “Our data clearly show that CIB1 is required for permitting activation of calcineurin during maladaptive cardiac hypertrophy. This suggests a new strategy for treating hypertrophic heart disease through inhibition of CIB1 or its interaction with calcineurin.”
Molkentin emphasized that the research is only one step toward combating cardiac hypertrophy. But the study’s findings, to be published in an upcoming edition of Nature Medicine, could help lead scientists to new, more effective therapies for a potentially fatal condition.
Scientists at Cincinnati Children’s have identified a novel molecular process that may help explain why some people with asthma suffer severe, hyper-inflammatory responses when exposed to allergens such as dust mites or cigarette smoke.
The study, published Aug. 29 in Nature Immunology, reports that the anaphylatoxin complements C5a and C3a – large glycoproteins that have important functions in the immune response system – play important roles in controlling production of the inflammatory agent interleukin-17 (IL-17A). A lack of C5a can result in an “amplification loop” that drives severe asthmatic reactions in mice bred genetically to mimic human disease. Meanwhile, reducing levels of C3a appears to limit inflammatory response.
“This study suggests that at some point it may be possible to treat or prevent severe forms of asthma by inhibiting pathways that drive the production of IL-17A,” says Marsha Wills-Karp, PhD, director of the Division of Immunobiology at Cincinnati Children’s and the study’s senior investigator.
The study involved exposing two sets of genetically engineered mice to house dust mite allergen extract.
One group of mice was bred to lack receptors for C5a, which normally prevents harmful responses to inhaled allergens. When exposed, these mice responded with high levels of IL-17A and severe airway inflammation. But when researchers blocked IL-17A production in this group, the mice had less airway hyper-responsiveness.
A second group of mice was deficient in receptors for C3a, which normally produces IL-23, a cytokine involved in producing inflammatory T-cells. These mice generally produced less IL-17A and experienced less airway hyperresponsiveness when exposed to allergens. But when researchers increased the amount of IL-17A in the airways of this group, the mice experienced greater airway hyper-responsiveness.
Both sets of mice help detail the role IL-17A plays in severe inflammatory responses. As IL-17A levels have been strongly associated with severe asthma in humans, these studies provide insight into the mechanisms driving severe asthma. Moreover, the studies suggest that controlling the complement IL-17A pathway may provide potential treatments for severe asthma.
A cardiac surgeon at Cincinnati Children’s may have a surprising explanation for why some babies are born with a devastating heart malformation.
Approximately one in every 8,000 infants in the U.S. is born with hypoplastic left heart syndrome (HLHS), a condition in which most of the left side of the heart is missing. About half of the infants do not survive; those who do often require multiple, complex surgeries.
Pirooz Eghtesady, MD, PhD, performs the complex surgeries required to repair HLHS, and his experience in the operating room has led him to identify a possible link between the disease and mothers’ histories of repeated strep throat infections.
Eghtesady began suspecting a connection between strep and HLHS about four years ago, when he noticed similarities in the damaged heart tissues of a newborn with HLHS and a 13-year-old child with valve damage – a possible effect of untreated strep infections – he had treated the day before. He decided to further investigate the possible link on a molecular level.
Analysis of tissue samples, performed in conjunction with a pathologist at the University of Oklahoma, revealed high levels of strep antibodies in the blood of several women who had infants with HLHS. Further analysis revealed that the antibodies were binding to heart cells in a location known to result in muscle damage.
Eghtesady has been awarded a five-year, $1.88 million grant from the National Heart, Lung and Blood Institute to study whether HLHS may be an after-effect of women suffering repeated strep throat infections during childhood. The project will compare data from 67 infants with HLHS to control groups of infants with other heart defects and to infants without heart disease.
“If this potential cause is confirmed, it raises a new avenue of research,” Eghtesady says. “For example, it could lead to screening tests to determine if a woman is at higher risk. It also could renew interest in developing a strep vaccine to prevent these cases.”
Cincinnati Children’s has been selected to lead an international study to track the long-term outcomes of children who use the arthritis medication abatacept (Orencia).
A grant of more than $4 million from Bristol- Myers Squibb, the drug manufacturer, will support an FDA-required Phase IV post-marketing surveillance trial that will involve up to 120 medical centers in the U.S. and worldwide. The study will follow a total of 800 patients for a decade.
In April 2008, the FDA approved using Orencia in children ages 6 and up as a treatment for moderate- to-severe juvenile ideopathic arthritis (JIA). A post-marketing study is required to check for rare side effects or complications that did not appear during initial clinical trials.
Orencia is one of several newer “biologics” introduced in recent years to control rheumatic diseases in adults and children.
“There has been an explosion of biologic therapies in the last 15 years,” says Daniel Lovell, MD, MPH, associate director of the Division of Rheumatology and principal investigator for the study. “These are large, complex man-made proteins designed to mirror natural biologic processes in humans.”
Most arthritis-related biologics block inflammatory mediators such as tumor necrosis factor (TNF). But Orencia blocks a receptor associated with the stimulation of T-cells, another part of the inflammatory process.
“The mechanism of action for Orencia is unique,” Lovell says. “This is attractive because it may work in patients in whom these other biologics do not work. But is also means we need to be vigilant in looking for new safety issues.”
Cincinnati Children’s was selected as the coordinating center for the Phase IV trial because the Division of Rheumatology has a long history of leading multi-center research studies. In fact, Cincinnati Children’s has been the headquarters of the Pediatric Rheumatology Collaborative Study Group since 1990.
“We have become a center for these large clinical trials because we have accumulated knowledge over the years on how to do them in children with arthritis,” Lovell says. “It’s not the same as conducting them in adults.”
The age of onset of puberty in girls continues to decline, according to a study published online in the Aug. 9 issue of Pediatrics.
The study found that the number of 7- and 8-year-old girls with breast development is greater than it was in studies conducted 10 to 30 years earlier, says Frank Biro, MD, director of adolescent medicineat Cincinnati Children’s and the study’s lead author.
“What causes earlier onset of puberty isn’t entirely clear at this time, but we are looking closely at several different potential factors, including genes and environmental exposures, as well as how those two may interact with each other,” says Biro.
Biro and his colleagues studied 1,239 girls between the ages of 6 and 8 from Cincinnati, East Harlem, N.Y., and San Francisco. The researchers used well-established criteria of pubertal maturation, including the five stages of breast development known as the Tanner Breast Stages.
The researchers found a higher prevalence of onset of breast development among girls at age 7 and 8, especially in white girls, compared to those observed in a study conducted just a few decades ago. Biro is now exploring whether environmental exposures and obesity might play a role.
“We think an important contributing factor might be the higher BMI (body mass index) in girls in this country,” Biro says.
Dr. Frank Biro wants to know why some girls reach puberty so much earlier today.
Previous studies have shown a link between an earlier age of menarche (first menstrual period) and an increased risk of breast cancer. “Earlier pubertal maturation doesn’t mean a girl will develop breast cancer,” Biro says. “But those girls with earlier onset of pubertal maturation are at a greater risk of breast cancer later in life.”
The study was conducted through the Breast Cancer and the Environment Research Centers, which were established in 2003 by the National Institute of Environmental Health Science and the National Cancer Institute
One of the first clinical trials of a genetically reprogrammed herpes simplex virus to treat deadly forms of cancer in children is underway at Cincinnati Children’s, supported by a $600,000 grant from the U.S. Food and Drug Administration.
The Phase I clinical trial focuses on testing the safety of the agent HSV1716 in patients. The study includes young patients with solid tumors such as rhabdomyosarcoma or Ewing’s sarcoma. These cancers have limited treatment options and survival rates under 30 percent when they spread to other parts of the body.
Survival curves for stubborn, metastatic childhood cancers have leveled off in the last decade, underscoring the need for new therapeutic approaches, says Timothy Cripe, MD, PhD, a researcher in the Divsion of Hematology / Oncology and principal investigator on the trial. The HSV1716 virus being tested was developed and produced by Crusade Laboratories of Glasgow, Scotland.
HSV 1716 has proven to be safe in adults in trials conducted in Europe, where it was tested first in animal models, then in adults with brain cancer, squamous cell carcinoma and melanoma. Cripe has conducted extensive testing for safety in animal models here, prior to potential use in children.
“We’ve exhausted our ability to improve cure rates in children with existing conventional therapies and we need new solutions,” Cripe says. “This is why we are testing HSV. It’s a potent virus that has been manipulated genetically with the intent of making it safe for the patient.”
The grant from the FDA is part of a program encouraging clinical development of so-called “orphan drugs” as new treatments for rare conditions.
HSV1716 is similar to other tumor-targeted viruses that are being used in early adult clinical trials. Certain genes are removed so the virus does not infect healthy dormant cells or cause the disease in the recipient. Instead, the genetic manipulation prompts the virus to target, infect and degrade only rapidly dividing cancer cells. These therapies are being studied by Cripe and colleagues at Cincinnati Children’s for their ability to kill pediatric tumors in the test tube and in mouse models.
Genetic information can be added to HSV to program the virus to attack cancer cells in a number of ways, such as activating certain types of chemotherapies in a one-two punch or destroying blood vessels that feed tumors. “Our goal is to light a fire to the cancer so that the virus replicates and spreads to the cancer cells,” Cripe explains. “We have to take this one step at a time and the initial phase of the trial focuses on making sure the virus doesn’t cause adverse side effects.”
He plans to enroll up to 18 patients in the Crusade Phase I trial, which is expected to last three years. The optimum safe dosing for this virus is unknown, so the study will sequentially increase dosing levels in small groups of patients, and observe for side effects, as the trial proceeds. This earliest phase tests the lowest dose, on older children and young adults with solid tumor cancers who have limited or no standard therapy options available. The researchers plan to add younger patients with earlier stages of cancer as the trial proceeds. They will not be able to determine if the safety trial is successful until all patients have received treatment and the results analyzed.
As with all clinical trials of new anticancer therapies in patients, many factors can influence the risk for severe side effects and anticancer activity. Even though HSV1716 may cause tumor shrinkage in mouse models of pediatric cancer, it may not have antitumor effect in patients.
“We are still at the beginning of a learning curve for this therapy and our patients are at the end stage of their disease,” says Cripe. “We want to get to where we are at the end of the learning curve, treating patients who are at the beginning stage of their disease. The only way to get there is through carefully conducted clinical research.”
Read more about the HSV1716 trial
Beyond obesity: Dr. Rohit Kohli has shown that high levels of fructose and trans fats contribute to fatty liver disease.
Scientists at Cincinnati Children’s have discovered that a diet with high levels of fructose and trans fats not only increases obesity, but also leads to significant fatty liver disease.
In a study published online in the journal Hepatology, researchers from Cincinnati Children’s and the Metabolic Disease Institute at the University of Cincinnati used a mouse model that closely replicates human obesity and liver disease to test the effect of unhealthy diets.
The study found that a 16-week diet of high fructose drinking water and trans-fat solids were significantly more likely to develop fatty liver disease than mice fed a standard mouse-chow diet for the same period. These mice also showed increased oxidative liver stress, inflammatory cells and fibrosis, all signs of fatty liver disease.
The study’s main author Rohit Kohli, MD, suggests that this mouse model could help scientists better understand and treat human fatty liver disease.
“Our data suggest that supplementation with pharmaceutical agents should be tested on our new model to establish whether one is able to reverse or protect against progressive liver scarring and damage,” Kohli says.
The study also uncovered a biomarker that, through a blood test, can indicate the progression of liver disease, Kohli says. Physicians currently use invasive liver biopsies to monitor the progression, so this discovery could lead to improved patient comfort when diagnosing liver disease.
