Alexander Bondoc, MD
Alexander Bondoc, MD
, is an investigator and pediatric surgeon in the Division of Pediatric General and Thoracic Surgery. Dr. Bondoc’s laboratory is investigating novel molecular pathways important in the development of aggressive hepatoblastoma (HBL), the most common primary liver tumor in children. The lab is currently investigating the role of Glypican 3 (GPC3) in development of HBL which may be pivotal in the discovery of novel therapies to treat patients as well as the importance of protein-protein interactions between GPC3, Delta like non-canonical Notch ligand 1 (DLK1) and insulin like growth factor 2 (IGF2) in HB tumor growth and proliferation. Additionally, Dr. Bondoc’s laboratory generates patient-derived xenografts (PDX) of human HBL and hepatocellular carcinoma (HCC) to augment understanding of the genotypic and phenotypic behavior of pediatric liver tumors. Used as an in-vivo method for pre-clinical studies, the use of murine models is also applicable for therapeutic testing and drug development.
Richard Falcone, Jr, MD, MPH
Pediatric trauma research includes work led by the research team at Cincinnati Children’s and as partners in several multi-center studies. The primary work led by our research team includes a multi-center study with 15 other sites examining the optimal resuscitation methods for pediatric patients. This important work will expand our knowledge of the appropriate timing and which type of fluid to utilize with the most severely injured children. The project received sponsorship from the Eastern Association for the Surgery of Trauma Multi-Center Trials group and received funding from the Childress Foundation. Other active studies include a study to examine the use of contrast-enhanced ultrasound, management of pancreatic trauma, and evaluation of blunt abdominal trauma. Additionally, our work in collaborating and supporting other developing/established pediatric trauma centers continues to drive quality improvement across centers. This program, the Pediatric Trauma Transformation Collaborative
(PTTC), has four partners within the US and maintains a partnership with a hospital in Poland which is striving to be the first pediatric trauma center in the country. Finally, our injury prevention work continues to explore the impact of our home safety program, and our national Buckle Up for Life
program focuses on reducing pediatric injuries. Our impact is far reaching with over 1,000 homes with our home safety program, and a presence in all 50 states and the Dominican Republic with our Buckle Up for Life Program. Toyota
provides generous funding for this important work.
Jason S. Frischer, MD
Jason S. Frischer, MD, is the director of the Colorectal Center and a pediatric surgeon within the Division of Pediatric General and Thoracic Surgery. Dr. Frischer is also director of the Extracorporeal Membrane Oxygenation (ECMO) Program. Dr. Frischer and the Colorectal Center recently published an article detailing their development and validation of a fecal incontinence-specific quality of life measure. Involuntary passage of stool is a problem that limits a child’s ability to participate in developmentally normative social and lifestyle activities and fecal incontinence may have an impact on emotional and social functioning. Parents also appear to experience a significant burden.
The high prevalence of fecal incontinence, combined with its psychological and social impact, is what led Dr. Frischer’s team to develop a comprehensive psychosocial assessment that considers parenting stress, activity limitation, and health-related quality of life (HRQoL). The name for this assessment is the Cincinnati Fecal Incontinence Scale (CINCY-FIS). After validating criteria and analyzing results of 222 patients, the CINCY-FIS proves to be a reliable and valid instrument for assessing parent-reported HRQoL and parenting stress in 3- to 12-year-old children who soil their clothing with feces. This tool is the first pediatric health-related quality of life measure that includes parent and patient experiences with fecal incontinence.
Dr. Frischer and his team also published a comparative study regarding surgical complications after appendicostomy and neoappendicostomy in pediatric patients. While appendicostomy and neoappendicostomy allow patients with a diagnosis of fecal incontinence to have a higher level of self-care, this study found that patients who undergo a neoappendicostomy are 1.8 times more likely to experience a major postoperative complication that required a surgical or interventional radiology procedure when compared to patients who undergo appendicostomy; however, the types of postoperative complications between the two procedures was similar. The Colorectal Center is currently studying the quality of life after these procedures, as well as how complications influence qualify of life .
Dr. Frischer and the Colorectal Center created a video titled “Sacral Nerve Stimulator Placement: A Novel Surgical Navigation Tool and Complex Anatomy,” which highlights the use of a hybrid operating room and the collaboration between colorectal surgery and interventional radiology in patients with complex pelvic anatomy. The most recent American Pediatric Surgical Association conference shared this video with attendees.
Michael Helmrath, MD
Michael Helmrath, MD
, focuses his career on complex gastrointestinal diseases. He actively participates in translational, and basic science research. He currently serves as the director of surgical research for Cincinnati Children’s. Dr. Helmrath currently oversees ongoing national and international clinical trials for intestinal failure and bariatric surgery. These studies include the GIFT’2, TeenLabs, ST20MP, and translational studies for both gastric disease and cystic fibrosis. His basic science laboratory
specifically focuses on the role of intestinal stem cells in small intestinal physiology. His work received continuously funding by multiple NIH awards since 2002. His U01 award, U01DK103117, aims to lead to a deeper understanding of regional influence within the intestinal stem cell populations that may contribute to physiological and disease specific differences commonly seen between the proximal and distal intestine. As part of the Intestinal Stem Cell Consortium
, he keeps actively involved in the intestinal stem cell field. His long-term research goal is to establish translational therapies for the management of patients with complex gastrointestinal diseases. Dr. Helmrath also serves as the director of clinical translation for the Center for Stem Cell & Organoid Medicine
(CuSTOM). In this role, Dr. Helmrath and other translation researchers use organoids derived from patients to understand mechanisms of disease and to identify new therapeutic targets.
Todd Jenkins, PhD, MPH
Todd Jenkins, PhD, MPH
, is an associate professor in the Division of Pediatric General and Thoracic Surgery, and director of the data coordinating center for Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS). His research focuses on obesity, surgical outcomes, and geographic information systems. He recently received a UM1 award from the National Institutes of Health, NIDDK
, titled “Continuation of Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS), Biostatistics Research Center” in collaboration with Changchun Xie, PhD
, associate professor of biostatistics in the Department of Environmental Health, at the University of Cincinnati
. The New England Journal of Medicine
(May 2019) recently published the latest findings from the Teen-LABS study.
Helen Jones, PhD
Helen Jones, PhD, and her lab members investigate the maternal-fetal interface in a broad range of pathologies, and are developing targeted gene therapy protocols to use during pregnancy to improve placental function and fetal growth. Dr. Jones and her team assumed responsibility for the previous collaborative study into the role of maternal immune modulation of placental invasion which led to publication in Science Immunology, and is continuing to expand the translational aspects of this project.
With R01 funding for the nanoparticle-mediated gene therapy project studies are continuing into the inclusion of a targeting peptide onto the nanoparticles for systemic delivery and incorporation of MiRNA seed sequences to address off-target effects. The expansion to include the use of a guinea pig model of fetal growth restriction to assess longer term in vivo treatment included the development of ultrasound-guided placental injection, a less-invasive technique significantly reducing surgery and recovery time for the animals. A successful collaboration with Natalia Schlabritz-Lutsevich, MD, PhD, at Texas Tech University Health Sciences Center, recently demonstrated trophoblast-specific nanoparticle uptake, without transfer to the fetus, in a perfusion model of human placenta, taking another step towards future use in the patient population. For further development of this project in the non-human primate Dr. Jones established a new collaboration with Thaddeus Golos, PhD, at the University of Wisconsin Madison, and recently begun analysis on samples following NHP nanoparticle placental treatments.
In collaboration with James Cnota, MD, and the Heart Institute, the Jones lab published significant alteration of placental development in cases of congenital heart defects (CHD), including hypoplastic left heart syndrome (HLHS), and transposition of the great arteries (TGA) in humans including the similarities and differences in the molecular mechanisms underlying disrupted concurrent placental and heart development in these subtypes of CHD. Members of the Jones lab are currently using mouse models to identify if changes in placental development may contribute to the etiology of congenital heart defects and in vitro human cell models to investigate disturbances in the development and signaling of the heart-placenta axis throughout gestation.
Dr. Jones maintained collaborations with Laura Woollett, PhD, UC Pathology, to study the effects of cholesterol on placental development and function, as well as collaborations with Louis Muglia, MD, PhD, in the Center for Prevention of Preterm Birth, to investigate placental involvement in preterm birth. These collaborations are fruitful leading to both impactful publications, and two successful NIH grant applications.
Maxime Mahe, PhD
Maxime Mahe, PhD
, is an assistant professor in the Division of Pediatric General and Thoracic Surgery. The overall goal of his research is to provide insight into the gastrointestinal development and the pathophysiology relevant to functional disorders including Hirschsprung disease. His research goals are to develop and study intestinal model systems using human pluripotent stem cells. An example of Dr. Mahe’s recent achievement was to engineer an enteric nervous system (ENS) in human intestinal organoids. In this context, the development of human intestine with an ENS represents a real opportunity to expand our knowledge into the effect of ENS on intestinal development and toward the understanding of pathophysiological processes leading to functional gastrointestinal neuropathies. As the complexity of the intestine is also tied to its environment, Dr. Mahe is also using these organoid systems to integrate a luminal environment with nutrients and microbes.
Jaimie Nathan, MD
Jaimie Nathan, MD
, surgical director of the Pancreas Care Center
, and his team established the total pancreatectomy and islet autotransplantation (TPIAT) program at Cincinnati Children’s for children with debilitating pain and impaired quality of life due to acute recurrent and chronic pancreatitis. He has ongoing research efforts in the surgical management of pancreatic diseases in children, and he is a collaborator with INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) with the overarching goal of gaining a better understanding of acute recurrent and chronic pancreatitis on a larger scale in order to develop future therapeutic studies. He is co-investigator on the R01-funded multi-center prospective observational cohort study of TPIAT (POST Study), with the the goal of addressing research gaps and developing future intervention studies regarding the surgical approach to and timing of TPIAT. In addition, with funding from the Cincinnati Children's Junior Cooperative Society, we will be investigating the role of intestinal microbiota in the progression of acute to acute recurrent to chronic pancreatitis and in the development of severe acute pancreatitis episodes.
Jose L. Peiro, MD, PhD
A research team led by Jose Peiro, MD, PhD, director of endoscopic fetal surgery at the Cincinnati Fetal Care Center, continues to investigate the basic mechanisms of pediatric and fetal surgical congenital malformations, focusing especially upon fetal myelomeningocele (MMC), congenital diaphragmatic hernia (CDH), and gastroschisis.
The focus of MMC is to improve the fetoscopic approach for intrauterine repair by evaluating different patches and sealants in large animal models in collaboration with biomedical engineers at the University of Cincinnati with professor Chia-Ying Lin's lab and then translating these techniques for use in the human fetus. Drs. Peiro and Lin recently received an award from R01 to support their research using an innovative “smart patch” for the fetoscopic procedure to repair MMC using a sheep model. In addition, a clinical trial is comparing fetoscopic MMC repair in humans versus the standardized open fetal surgery approach. An MRI prenatal assessment is in process to analyze the early anatomic improvements after fetal surgery for MMC. Researchers are determining the mechanistic processes, and pathways activated, in the neuro-inflammation and neurodegeneration that appear in open neural tube defects by means of rodent and sheep models. The team is also studying ways to use neural progenitor cells collected from the cerebrospinal and amniotic fluid of MMC patients as a potential form of neural regeneration (cell therapy). In collaboration with Dr. Shaaban’s lab in Chicago, they are using a mouse model of neural tube defects to investigate how maternal immune status can influence on incidence of congenital malformations.
Evaluating Fetal Surgery to Support Lung Development
Dr. Peiro’s lab continues to study animal models that indicate early fetal tracheal occlusion may induce faster and better fetal lung growth. They described comparison of a novel surgically-induced CDH model in rats with gene-expression to the teratogen nitrofen-induced CDH model in a collaborative study with Jeffrey Whitsett, MD, and his research group. This group is using rodents to determine a new radiologic prenatal and postnatal biomarker by 3D lung assessment for better prognosis of pulmonary hypertension. In collaboration with Brian Varisco, MD, and his lab, the Peiro lab is investigating molecular pathways involvement in lung growth after tracheal occlusion by proteomics in rabbit and sheep models. Moreover, they continue to clinically offer fetoscopic tracheal occlusion in human fetuses with severe CDH by detachable balloon insertion. This work will contribute to an ongoing multi-center TOTAL trial.
Neuroenteric and Lymphatic Disorders Related to Gastroschisis
In gastroschisis, researchers are analyzing the neurodegenerative and lymphatic anomalies that associate with fetal gastroschisis, and their relation with intestinal hypomotility and malabsorption in the fetal rabbit model. They are also studying the origin and presence of intrauterine growth restriction in these fetuses with gastroschisis in collaboration with Mounira Habli, MD, and Dr. Jones’ lab.
Soona Shin, PhD
Soona Shin, PhD
, is a member of the Liver Tumor Program. Her research aims to decipher the molecular and cellular mechanism of childhood liver cancer with a focus on facultative hepatic progenitor cells, fetal hepatoblasts, and hepatocytes. Facultative postnatal hepatic progenitor cells and fetal hepatoblasts are tissue-specific stem cells that can differentiate into hepatocytes and cholangiocytes, the two major epithelial cell populations in the liver. The research team investigates the hypothesis that while hepatic progenitor cells promote pathological angiogenesis, dysregulated differentiation of both fetal hepatoblasts and hepatocytes initiates tumorigenesis. The Shin lab
employs molecular genetic approaches to test this hypothesis and collaborates with Drs. Timchenko, Bondoc, and Gupta to discover novel strategies for prevention and treatment of liver cancer.
Gregory Tiao, MD
Gregory Tiao, MD, is the director of the Division of Pediatric General and Thoracic Surgery and surgical director of liver transplantation. Dr. Tiao is also a member of the Liver Tumor Program, and a member of the Children’s Oncology Group Rare Tumor Liver Subcommittee. Dr. Tiao’s lab, including Sujit Mohanty, DVM, PhD, along with research assistants Bryan Donnelly and Haley Temple, continues work on the pathogenesis of biliary atresia through a recently renewed R01 grant. Specifically, this grant focuses on how the amino acid sequence “SRL” (445-447) found within the VP4 protein of certain strains of rotavirus utilizes a unique receptor on the surface of the cholangiocyte and dendritic cells governing intracellular trafficking of the virus resulting in activation of an innate immune response and the release of the alarmin HMGB1. The sequence “SRL” is also present on one of the attachment proteins of certain strains of cytomegalovirus (CMV), reovirus, Epstein-Barr virus (EBV), and HPV. There is isolation of all of these viruses from patients with biliary atresia.
Generation of a novel rotavirus strain resulted in a manuscript entitled “Rotavirus reassortant induced murine model of liver fibrosis parallels human biliary atresia” recently submitted for publication. This manuscript details the use of a reassortant rotavirus injected into newborn mice that causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3-5 fibrosis with histopathological signs of inflammation/fibrosis and bile-duct obstruction. This model is different from carbon tetrachloride injection and duct ligation models and liver gene expression pattern shows similarities to human biliary atresia. This novel model of rotavirus-induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to identify novel therapeutic targets that may alter the course of biliary atresia.
Dr. Tiao, along with James Geller, MD, are study co-chairs on the Children’s Oncology Group (COG) Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT). The expectation is for this trial to run for the next five years and accrue 500 patients in North America with a total of 1,200 participants across the world.
Nikolai Timchenko, PhD
Nikolai Timchenko, PhD, is a professor in the Division of Pediatric General and Thoracic Surgery at Cincinnati Children's and UC Department of Surgery. He is also the head of Liver Tumor Biology for the Liver Tumor Program. His lab investigates mechanisms of hepatoblastoma (HBL), hepatocellular carcinoma (HCC), and mechanisms of non-alcoholic fatty liver disease (NAFLD).
Liver Cancer: The origin of liver cancer is under intensive investigations; however, there is little known about tumor originating cell types and mechanisms which initiate aggressive pediatric liver cancer. Dr. Timchenko’s lab generated five unique animal models with accelerated or inhibited liver cancer after treatments with certain carcinogens. Investigations of molecular pathways in these animal models showed that de-differentiation of hepatocytes into stem-like cells is the origin of hepatocellular carcinoma. In collaboration with Drs. Tiao and Bondoc within the division; Dr. Geller from the Division of Oncology; Anita Gupta, MD, from the Division of Pathology; and other members of the Liver Tumor Program, Dr. Timchenko analyzed a large cohort of liver samples from patients with HBL discovering molecular basis for two types of HBL. He found that classic (mild) HBL is the result of a failure of hepatic stem cells to differentiate into hepatocytes and that there is an association with this failure with the activation of FXR-Gankyrin axis. Dr. Timchenko found that aggressive (chemo-resistant) HBL is the result of de-differentiation of hepatocytes into stem-like cells. His recent studies identified a unique genomic domain (Aggressive Liver Cancer Domain, ALCD) which activates many cancer-related pathways. Dr. Timchenko’s lab found that this domain is under control of PARP1 protein and that aggressive hepatoblastomas utilize PARP1-ALCD axis to elevate the mutant beta-catenin and NRF2 genes as well as many other oncogenes. Current studies focus on identification of liver cells with the activation of ALCDs, and the precise mechanisms of activation of these domains. These mechanisms are complex and associate with several transcription factors, including modified ph-S6-p53, that deliver the PARP1 complex to ALCDs. Dr. Timchenko’s lab recently showed that development of another liver cancer, fibrolamellar carcinoma (FLC) might also involve the activation of ALCDs. Future studies will focus on the development of drugs to inhibit aggressive HBL by inhibiting the ph-S6-p53-PARP1-ALCD pathway and mechanisms of activation of ALCDs in FLC. These studies translate the knowledge of the molecular mechanisms of liver cancer generated in animal models to clinical application in human patients.
NAFLD: Investigations of NAFLD by Dr. Timchenko’s lab resulted in the discovery of a triggering event that causes NAFLD. This event is the elevation of cdk4 and subsequent stimulation of a cascade of pathways that lead to NAFLD. Dr. Timchenko also found that the inhibition of cdk4 prevents/reverses early steps of NAFLD in animal models. Recent investigations by Dr. Timchenko’s lab reveal that cdk4 inhibitors also correct age-associated steatosis and many other age-related liver disorders. Since the FDA approved the use of cdk4 inhibitors, and they are in clinical trials for liver cancer, it is possible to initiate clinical trials for NAFLD with these drugs. These discoveries received extensive media coverage. Since cdk4 is a strong promoter of liver proliferation, Dr. Timchenko’s lab investigated the role of proliferation in NAFLD using two animal models with inhibited and accelerated liver proliferation. These studies found that liver proliferation, but not steatosis, is an essential driver of high fat-mediated fibrosis. Hepatology Communications recently published this discovery. Since the obesity-associated NAFLD represents the most common cause of pediatric liver fatty disease, the ongoing studies in Dr. Timchenko’s lab focus on the role of liver proliferation in pediatric fatty liver disease and mechanisms of this disease.