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On July 15, 2013, leaders of pediatric research institutions across the country sent a letter to members of Congress asking that they restore National Institutes of Health (NIH) funding for pediatric research. The Director of our Research Foundation, Arnold Strauss, MD, was among them. Following is an excerpted version of the letter.
Dear Members of the U.S. Congress and U.S. Senate:
We write in opposition to sequestration and to strongly urge restoration of funding cut by it. ...As you work on the FY 2014 budget, seek restoration to FY 2012 pre-sequestration levels. NIH-funded pediatric researchers are working every day to find cures for children with devastating illnesses such as cancer, to develop interventions that promote health and longevity for children with lifelong chronic illnesses such as cystic fibrosis, and to find the scientific keys to preventing conditions that appear on the rise and worry us all, such as autism.Children make up 30% of the US population, yet pediatric research represents only 6% of NIH directed dollars. If you are the parent, grandparent, teacher or friend of a child with … any one of the hundreds of pediatric diseases or illnesses currently under investigation and funded by the NIH, the day-to-day urgency of this research is high... It is often truly a matter of your child’s life or death.Largely due to the disproportionately low amount of funding for pediatric research, a significant amount of what pediatricians are required to practice is based on information derived only from studies in adults. It is a hazardous reality that medications ranging from pediatric antibiotics to anti-depressants are in fact frequently just adult drugs dosed-down for children.The sequestration cutbacks threaten to reduce children’s access to currently available clinical trials, and stalled advancements in pediatric research threaten delays in the development of new treatments and therapies to cure diseases in children and youth. Recent and emerging discoveries related to early predictors of childhood disease and risk for adult onset of certain diseases would go underutilized because funding for critical research to validate and translate for clinical use would be cut.
NIH cuts under sequestration are indiscriminate and arbitrary. Scientific research can’t be switched on and off on a dime and continue to yield results. It requires predictable and sustained support that isn’t possible when drastic, across-the-board cuts like sequestration are imposed… In-progress research will be disrupted, delaying the achievement of new medical breakthroughs. Pediatric research is the path toward preventing chronic adult disease. Please restore NIH funding cuts that will delay discovery of urgently needed cures to childhood diseases.
Scientists at Cincinnati Children’s have successfully targeted a malfunctioning immune system enzyme and killed diseased cells from patients with myelodysplastic syndromes (MDS), a group of blood disorders in which the bone marrow does not produce sufficient healthy blood cells.Researchers reported July 8 in Cancer Cell that the immune system enzyme IRAK1 (Interleukin Receptor Associated Kinase-1) is over-expressed and hyper-activated in about 25 percent of MDS cells. The researchers tested the effect of blocking IRAK1 using a small-molecule inhibitor developed initially as a treatment for autoimmune disease and chronic inflammation.“Not only does our research implicate errant immune system signaling in MDS cells, it strongly indicates that inhibiting the function of this hijacked immune pathway may become an effective treatment option for MDS,” says Daniel Starczynowski, PhD, Division of Experimental Hematology and Cancer Biology, who led the study.Both genetic and pharmacologic inhibition of IRAK1 slowed the progression of human MDS cells and in mouse models of the disease. Inhibiting IRAK1 had no effect on normal human blood cells, showing it selectively targets MDS cells.MDS is a group of syndromes in which a person’s blood stem cells do not mature into healthy red or white blood cells. Instead, they die off in the bone marrow or blood, leaving an insufficient number of healthy cells in the body. This can cause infections, anemia, bleeding disorders or acute myeloid leukemia (AML).The disorders affect children but are more common in people over the age of 60. So far, the only cure for MDS is bone marrow transplant.Starczynowski cautions that successful laboratory tests do not necessarily translate into effective treatments. And because IRAK1 is currently thought to be over-expressed in a subset of MDS patients, any drugs targeting the enzyme would in theory benefit only that group. Nevertheless, he is optimistic and his team will continue their studies.“There is an urgent need to develop new targeted therapies that can eliminate MDS-initiating clone cells and provide a durable therapeutic response.”
Team effort cuts incidence of ulcers in half When a study revealed that more than 10 percent of children in our intensive care units experienced pressure ulcers, Cincinnati Children’s took action.The hospital formed a quality improvement (QI) collaborative leadership team and implemented a QI “bundle” of solutions. The goal, and the result, was to reduce pressure ulcers among children hospitalized in the pediatric intensive care units by 50 percent within one year. The study, led by Marty Visscher, PhD, Director of the Skin Sciences Program, was published July 23 in Pediatrics.The team found that the causes of pressure ulcers in children are different than in adults. Although most pressure ulcers in adults occur due to pressure on bony parts of the body, pressure ulcers in children occur largely because of ill-fitting medical devices that are not designed for children, but must be adapted to them.Those devices include facemasks used for mechanical ventilation, tracheostomy tubes, endotracheal tubes and orthopedic casts. Use of these devices is higher in critically ill patients, causing increased infection, pain and prolonged hospitalization.Successful interventions included thorough staff training, daily head-to-toe skin assessments, teaching parents about skin care and identifying “skin champions” on each unit, nurses with a particular interest in skin and wound care who serve as resources to staff on the unit.The study was co-authored by Sundeep Keswani, MD, Director of the Pediatric Advanced Wound and Skin Service, which provides wound treatment throughout the medical center and conducts research on skin and wound healing.
Insulin could be the reason why many mothers have difficulty making enough milk to breastfeed, says a study by scientists at Cincinnati Children’s and the University of California - Davis.Published in July in PLOS ONE online, the study describes how the human mammary gland becomes sensitive to insulin during lactation and how specific genes are switched on in the gland during lactation.The researchers used RNA sequencing to reveal a detailed blueprint for making milk in the human mammary gland, according to Laurie Nommsen-Rivers, PhD, a scientist in the Division of Neonatology and Pulmonary Biology at Cincinnati Children’s and corresponding author of the study. Lead author was Danielle Lemay, PhD, of the University of California – Davis Research Center.In earlier research, Nommsen-Rivers had shown that producing breast milk is more difficult for mothers who have markers of poor glucose metabolism – being overweight, of an advanced maternal age, or having a large birthweight baby. This suggested a role for insulin in the mammary gland. The new findings show how the mammary gland becomes sensitive to insulin during lactation.
“This new study shows a dramatic switching on of the insulin receptor and its downstream signals during the breast’s transition to a biofactory that manufactures massive amounts of proteins, fats and carbohydrates for nourishing the newborn baby,” says Nommsen-Rivers. “Considering that 20 percent of women between 20 and 44 are pre-diabetic, it’s conceivable that up to 20 percent of new mothers in the United States are at risk for low milk supply due to insulin dysregulation.”Capturing mammary gland RNA in samples of human breast milk, the researchers created a library of genes expressed in the mammary gland based on RNA-sequencing technology. They discovered an orchestrated switching-on and -off of various genes as the mammary gland transitioned from secreting immunity-boosting colostrum to the copious production of milk in mature lactation.Specifically, the protein tyrosine phosphatase, receptor type, F gene, known to suppress intracellular signals that are usually triggered by insulin binding to its receptor on the cell surface, may serve as a biomarker linking insulin resistance with insufficient milk supply. These results lay the foundation for future research focused on the physiological contributors to mothers’ difficulties with milk supply.The scientists plan a phase I/II clinical trial with a drug used to control blood sugar in type 2 diabetes to determine whether it improves insulin action in the mammary gland and increases milk supply.
Six research projects that show promise for commercial development have been selected to share $500,000 from the Innovation Fund at Cincinnati Children’s and $100,000 from the Greater Cincinnati Foundation.
The fund – now in its second year – provides early-stage bridge funding to further develop discoveries into medically and commercially viable products ready for outside investment.“The Innovation Fund allows the medical center to select promising projects developed by its researchers and accelerate their bench-to-bedside transition and entry to the patient care market,” says Niki Robinson, PhD, Assistant Vice President of the Center for Technology Commercialization (CTC). “This funding provides crucial financial support at a critical time to projects that otherwise might not continue their development.”
The Funded Projects
Ted Denson, MD, GastroenterologyA diagnostic technology that distinguishes between Crohn’s disease and ulcerative colitis.Punam Malik, MD, Experimental Hematology and Cancer BiologyAn improved γ-globin gene developed for a prospective Phase I/II clinical trial of gene therapy for sickle cell disease.Charles Dumoulin, PhD, RadiologyNeonatal MRI scanner for premature babies too fragile to transport beyond the NICU.William Hardie, MD, Pulmonary MedicineA prospective oral therapy that would target a specific molecule (P70S6K) to reverse pulmonary fibrosis.Senthil Sadhasivam, MD, MPH, AnesthesiaA rapid point-of-care genetic test and decision support tool that allows physicians to precisely tailor the use of opioids for pain management.Hector Wong, MD, Division of Critical Care Medicine A diagnostic biomarker (IL-27) for rapid and early identification of sepsis in patients.
In a study published in July online in The Journal of Infectious Diseases, Margaret Hostetter, MD and a team of researchers revealed that they have found an agent that could potentially prevent the Candida infections that often afflict hospitalized patients on central lines. Earlier research by Hostetter’s team showed that the heparin fed through central lines to prevent clotting binds with the Candida albicans yeast that lives on and in all of us. Candida uses the binding to elude the body’s immune response and to form biofilms – communities of microorganisms that grow on the inside surface of the catheters. Biofilms are the first step in bloodstream infections with the yeast.Hostetter and her team developed an antibody that prevents Candida albicans from binding with heparin and thereby stops biofilm formation in a rat model of catheter-associated infection.“Understanding how the medications in catheters facilitate biofilm formation by microbes can lead to new strategies for prevention of line infections,”says Hostetter.Her collaborators on the study included researchers from Duke University Medical Center, the University of Cincinnati, and the University of Wisconsin. When the antibody is modified to be compatible with humans, clinical trials of the treatment can begin in humans.
Harinder Singh, PhD, joins Cincinnati Children’s this fall as Director of Immunobiology. Singh is an expert on regulatory proteins that enable self-renewing pluripotent hematopoietic stem cells to generate various cells of the immune system. His laboratory focuses on genetic and molecular analyses of transcription factors that regulate the differentiation of immune cells.
Before coming to Cincinnati Children’s, Singh worked in the Department of Discovery Immunology at Genentech in San Francisco, where he oversaw drug discovery and development projects in Immunology. Prior to that, he was a member of the faculty of the University of Chicago as Louis Block Professor of Molecular Genetics and Cell Biology, Investigator with the Howard Hughes Medical Institute, and Chair of the Committee on Immunology. Singh says he accepted the appointment at Cincinnati Children’s in large part because he was interested in returning to the front end of the biomedical enterprise with a focus on the analysis of human diseases, particularly those that afflict children, and in developing new therapeutic approaches for them.“Deep down, I’m really a basic scientist. Curiosity about biological systems and processes in health and disease stimulates my thinking,” Singh says. “I’ve seen and experienced the whole biomedical spectrum of basic, translational and clinical research and I believe that the fundamental research needed to enable generation of transforming new drugs is best done in the academic sphere.”One of Singh’s goals is to build a Center for Systems Immunology that will harness approaches from Systems and Synthetic Biology to better understand the abnormal functioning of human immune cells in inflammatory and autoimmune diseases and eventually to use molecularly engineered immune cells for therapeutic purposes.Singh obtained his PhD from Northwestern University in 1984, working with Lawrence Dumas in Biochemistry and Molecular Biology. He also worked with two Nobel Prize winners in his years at the Massachusetts Institute of Technology (MIT); as a Jane Coffin Childs postdoctoral fellow with Phillip Sharp from 1984 to 1988 and in collaborations with David Baltimore’s laboratory, which sparked Singh’s interests in molecular and developmental immunology.Singh served as editor of Molecular and Cellular Biology from 1997-2007. He has been a member of the Board of Scientific Counselors for the National Cancer Institute (2002-2007) and an advisor to the California Institute for Regenerative Medicine (2006-2009).
Everolimus shows new promise for patients with tuberous sclerosis complexA drug originally developed to prevent the rejection of transplanted organs has dramatically reduced seizures in patients with tuberous sclerosis complex (TSC). A genetic disease characterized by benign tumors on multiple organ systems, TSC is estimated to affect more than 1 million people worldwide.The study is the latest to demonstrate the effectiveness of everolimus for TSC patients. Previous studies at Cincinnati Children's showed that the drug reduced tumors’ size in the brain and kidneys.The newest study, led by Darcy Krueger, MD, PhD, a pediatric neurologist and researcher at Cincinnati Children’s, has been published online in the Annals of Neurology. Krueger conducted the research in collaboration with a team at Texas Children’s Hospital in Houston.The study included 20 patients, median age of 8 years, who were treated with everolimus. Half were enrolled at Cincinnati Children’s and half at Texas Children’s Hospital.Everolimus reduced seizure frequency by at least 50 percent in 12 of the 20 children in the study. The drug also reduced seizures in 17 of the 20 children by a median rate of 73 percent. Four were free of seizures and seven had at least a 90 percent reduction in seizure frequency. The children’s parents reported other positive changes including improved attention and behavior.“The treatment reduced seizure frequency and duration for patients whose seizures previously did not respond to treatment,” says Krueger. “The improvement in seizure control was associated with a better quality of life, and side effects were limited.”Studies in the 1990s traced the cause of TSC to defects in two genes, TSC1 and TSC2. When these genes malfunction, the cell has higher activity of mTOR, a protein known to trigger uncontrolled tumor cell and blood vessel growth. Everolimus shrinks tumors by inhibiting mTORC1 and appears to reduce seizures in TSC patients in the same way.Krueger says work is already underway to confirm the results in a follow-up, phase III clinical study. Whether the drug will have the same positive effect on other types of epilepsy remains to be seen.“It is unclear whether the benefit of everolimus in treating epilepsy might extend beyond that observed in TSC,” says Krueger. “Additional clinical trials might tell us whether everolimus would benefit patients with epilepsy not related to TSC.”Funding for the study was provided by Novartis Pharmaceuticals and the Clack Foundation.
A program of education and technological intervention successfully reduced inappropriate antibiotic prescribing for community-acquired pneumonia (CAP), according to a study published in Pediatrics in May 2013. Lilliam Ambroggio, PhD, MPH, Division of Hospital Medicine, was lead author on the study. The goal of the program was to increase adherence to the appropriate antibiotic therapy for CAP as recommended in the Pediatric Infectious Disease Society/Infectious Disease Society of America’s national guidelines. Ambroggio’s team tracked patients’ antibiotic therapy starting six months prior to implementing their first intervention and for nine months after. A total of 217 children with pneumonia were eligible for the study. Within six months of introducing the program, providers at Cincinnati Children’s were meeting the antibiotic recommendations from the guideline for CAP in 100 percent of patients.“Changing the antibiotic prescribing habits of providers is difficult. To say that our results were better than anticipated would be quite an understatement,” Ambroggio says.The team educated physicians on the new antibiotic recommendations and created a quick reference guide. They also updated the hospital’s electronic medical records to default to the recommended antibiotics when a patient was diagnosed with pneumonia. Before the change, the default antibiotic was a broad spectrum drug.Ambroggio reports that the hospital has maintained near-perfect adherence to the guideline recommendations, which she attributes to a culture that is open to change, the defaults in the electronic records system and other high-reliability interventions. Her team is now investigating the health outcomes associated with adherence to the antibiotic recommendation.
Shuk-Mei Ho, PhD, will lead the Cincinnati Cancer Center (CCC), a new collaborative endeavor encompassing the activities of the Cancer and Blood Diseases Institute at Cincinnati Children’s, the University of Cincinnati (UC) Cancer Institute and UC Health. The CCC aims to create a comprehensive, collaborative center designated by the National Cancer Institute that leads in innovative research to eliminate cancer.Ho is Jacob G. Schmidlapp Chair of Environmental Health at the UC College of Medicine. She is known for her study of the role of hormones, endocrine disruptors and epigenetics in cancer development as well as her exploration of the interaction between genes, the environment and cancer. She will continue this work while overseeing the CCC’s research activities, which will focus on programmatic themes of discovery, translational and population sciences.
A biomarker test developed at Cincinnati Children’s to identify early acute kidney injury (AKI) in patients following surgery has now proven successful in broader clinical use.In a study published in the September Clinical Journal of the American Society of Nephrology, the test, which measures the biomarker neutrophil gelatinase-associated lipocalin (NGAL), was used to successfully diagnose AKI in adult patients with a variety of illnesses who were admitted to hospital from the emergency department.Prasad Devarajan, MD, Director, Division of Nephrology and Hypertension, developed the test and led the study, with collaborators at Fernando Fonseca Hospital in Portugal.The study demonstrated that the NGAL test, which uses a single drop of blood and provides results within 15 minutes, could accurately distinguish AKI from transient reversible kidney dysfunction. Of 616 patients who participated in the study, individuals who were subsequently diagnosed with true AKI had the highest levels of NGAL measured at the time of hospital admission. The study also identified a cutoff point in NGAL levels above which the risk of acute kidney injury increases tenfold.
Results of a study previously published (2008) by Devarajan and his team showed that the NGAL test predicted AKI in pediatric heart surgery patients within hours instead of days, allowing treatment that prevented serious damage to kidneys. Prior to the NGAL test, serum creatinine was the only reliable method for detecting kidney damage; however, the time delay until a rise in serum creatinine was apparent often resulted in permanent kidney damage.
With a growing number of patients coming to emergency rooms with community-acquired AKI, Devarajan says having a rapid, reliable method of detecting kidney injury is increasingly important.“This latest study showed that this simple laboratory test provides an early prediction of acute kidney injury and its severity in a heterogeneous clinical setting,” says Devarajan. “The identification of biomarkers that differentiate intrinsic AKI from transient reversible forms of renal dysfunction and predict outcomes is a high priority.”
Craig Erickson, MD, Psychiatry, received a three-year grant of $1 million from the John Merck Fund to study “Acamprosate in Fragile X Syndrome.”David Franz, MD, Neurology, received $1.1 million from Novartis Pharmaceuticals for a five-year efficacy and safety study of everolimus in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures.Xi Jason Jiang, PhD, Infectious Diseases, was awarded a five-year, $910,007 grant by the US Department of Agriculture to study “Universal Flu Vaccine by a Norovirus P Particle Platform” with the University of Cincinnati.Tatiana Kalin, MD, PhD, Neonatology and Pulmonary Biology, will use a four-year grant of $870,000 from the American Cancer Society to study “Transcriptional regulation of cancer progression and metastasis by FoxM1.”Raphael Kopan, PhD, Developmental Biology, will study “Assessing the Therapeutic Window for Future Anti-Notch Dimerization Agents” with a $1.6 million, five-year grant from the National Cancer Institute.Keith Marsolo, PhD, Anderson Center for Health Systems Excellence, will develop a “CMS Partnership for Patients Initiative” with the help of a three-year, $3.3 million grant from the Department of Health and Human Services.Louis Muglia, MD, PhD, Center for Preterm Birth, received $1 million from the March of Dimes Prematurity Research Collaborative, part of a five-year, $10 million statewide grant to fund research into prematurity.Avani Modi, PhD, Adherence Psychology, received a five-year, $3.6 million grant from the National Institute for Child Health and Human Development to study “Supporting Treatment Adherence Regimens in Pediatric Epilepsy.”
Jeffrey Whitsett, MD, Neonatology and Pulmonary Biology, will use $2.6 million awarded by the National Heart, Lung and Blood Institute over five years to pursue “Transcriptional Programming of Asthma-Related Pathology.”Gurjit (Neeru) Khurana Hershey, MD, PhD, Director, Division of Asthma Research, has been accepted into the Association of Medical School Pediatric Department Chairs’ (AMSPDC) Pediatric Leadership Development Program cohort for 2014-15. The yearlong fellowship program, which begins in February 2014, is designed to help develop the next generation of pediatric chairs in North America.Erna Olafson, PhD, PsyD, Mayerson Center for Safe and Healthy Children, was recognized by the American Professional Society on the Abuse of Children (APSAC) for outstanding service and commitment within the field of child maltreatment during the Society’s Annual Colloquium this past June.
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