Alexander Bondoc, MD

Bondoc is an investigator and pediatric surgeon in the Division of Pediatric General and Thoracic Surgery. 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 and other proteins important to the Wnt/β-catenin. Additionally, Bondoc’s lab 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, 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 Journal of Trauma and Acute Care Surgery recently published our recent multi-center study on the optimal resuscitation of pediatric patients. The Eastern Association for the Surgery of Trauma noted this as a “Landmark Paper.” This year, under the leadership of Meera Kotagal, MD, MPH, we began important work examining social determinants of health impacting injury rates and hospital bed days among children in our community. Utilizing the findings of this work will inform important interventions to reduce injury rates among children disproportionately impacted. Funding of this work is through a Place Outcomes grant from Cincinnati Children’s and an Ohio Department of Public Safety grant. 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 U.S. 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 with generous funding provided by Toyota for this important work. Toyota provides generous funding for this important work.

Jason Frischer, MD

Frischer is the director of the Colorectal Center and a pediatric surgeon within the Division of Pediatric General and Thoracic Surgery. Frischer is also director of the Extracorporeal Membrane Oxygenation (ECMO) Program. 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 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.

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.

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, MS

Helmrath 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. 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. Helmrath also serves as the director of clinical translation for the Center for Stem Cell & Organoid Medicine (CuSTOM). In this role, 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

Jenkins 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.

Meera Kotagal, MD, MPH

Kotagal is a pediatric surgeon in the Division of Pediatric General and Thoracic Surgery and associate director for Pediatric Trauma Services. Kotagal's interest is in variation in care and outcomes, and in how we can reduce the associated disparities. Her research focuses on disparities in injury-related morbidity and mortality, and interventions used to close that gap. Through funding from a Place Outcomes Research Award and an Ohio Department of Public Safety, EMS Research grant, Kotagal is examining, at a neighborhood level, the social determinants of health that underlie and drive pediatric injury in the Cincinnati region and State of Ohio. The results will use this work to understand the broader contextual factors driving who gets injured and how severe those injuries turn out to be. In particular, this work will identify hot spots of injury and the social determinants of health which may be driving these injuries. This critical information will help to develop community-based interventions, in partnership with community members and the injury prevention team at Cincinnati Children's Intestinal Care Center, as well as the All Children Thrive Network, to reduce pediatric injury.

Sujit Mohanty, DVM, PhD

Mohanty is an assistant professor in the Division of Pediatric General and Thoracic Surgery. The overall goal of his research is to understand the mechanism of virus-induced liver fibrosis in biliary atresia. He has developed a new mouse model to study liver fibrosis which was recently published in Hepatology. His research goal is to develop therapeutics which can prevent or delay liver fibrosis in biliary atresia patients. Mohanty is a co-investigator in Tiao’s R01 grant studying immune pathogenesis of biliary atresia. Mohanty, along with Tiao, have begun work on a project related to the current COVID-19 pandemic, primarily focusing on the SARS-CoV-2 interaction with liver cells.

Jaimie Nathan, MD

Nathan, 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. His ongoing research efforts are 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 a co-investigator on the R01-funded multi-center prospective observational cohort study of TPIAT (POST Study), with 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 Peiro, MD, PhD

A research team led by Peiro, the 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), hydrocephalus (HCP), and gastroschisis.

Innovative Therapies on Fetal MMC
The focus of MMC research 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. Peiro and Lin recently received an award from R01 to support their research using a new designed 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 also 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). Finally, in collaboration with Aimen Shaaban’s lab at the Ann & Robert H. Lurie Children's Hospital of 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
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. We’re exploring the fetal lung metabolism in the CDH fetal subjects that drives to hypoplasia and vascular maldevelopment. Our group is using rodents to determine a new imaging 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 rat, 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 new multi-center clinical trials.

Tacking Brain Damage by Prenatal Intervention in Fetal Hydrocephalus
One of the more attractive and disruptive research implemented in the Peiro Lab is the study of endoscopic third ventriculostomy (ETV) to prenatally treat congenital obstructive hydrocephalus (HCP) in a large animal model like the fetal lamb. With the conjunction of an experienced fetal surgeon (Peiro), pediatric neurosurgeon (Sono Duru, MD), and basic neuroscientist (Marc Oria, PhD), we’re advancing fast in this field since we started six years ago. We developed a new obstructive fetal HCP by injecting BioGlue in the fetal cisterna magna in sheep that serves as a perfect model for try and optimize fetal ETV to arrest the progressive cellular and molecular brain damage in HCP.

Neuro-enteric and Lymphatic Disorders Related to Gastroschisis
In gastroschisis, researchers are analyzing the neurodegenerative and lymphatic anomalies that associate with fetal gastroschisis, and their relationship with intestinal hypomotility and malabsorption in the fetal rat, rabbit and guinea pig models. They are also studying therapeutic in-utero strategies to improve the prognosis of these patients.

Soona Shin, PhD

Shin 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 Timchenko, Bondoc and Anita Gupta, MD, to discover novel strategies for prevention and treatment of liver cancer.

Gregory Tiao, MD

Tiao is the director of the Division of Pediatric General and Thoracic Surgery and surgical director of liver transplantation. Tiao is also a member of the Liver Tumor Program, and a member of the Children’s Oncology Group Rare Tumor Liver Subcommittee. 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 human papillomavirus (HPV). The thought is that these viruses associate in patients with biliary atresia.

Evaluation of the cholangiocyte response to rhesus rotavirus (RRV) infection resulted in a manuscript entitled “Cholangiocyte release of HMGB1 mechanistically governs the pathogenesis of murine model of biliary atresia and correlates with increased levels found in afflicted infants” recently submitted for publication. This manuscript details the release of HMGB1 from cholangiocytes was RRV VP4 dependent and a function of the phosphorylation of STAT-1 by p38. Further upstream to this pathway, we observed that RRV infection resulted in an increase in reactive oxygen species (ROS) levels and treatment with a ROS inhibitor, not only reduced p38 phosphorylation but also HMGB1 release. Similarly infection of human cholangiocytes also revealed a similar VP4 dependent release of HMGB1, suggesting a human correlation with the mouse model. Analysis of human protein array data collected from biliary atresia patients at time of Kasai, yielded a subset of patients with higher level of HMGB1, which we designated “High HMGB1” group. Interestingly those patients with “High HMGB1” had a higher three month total bilirubin level following Kasai when compared to those patients with a “Low HMGB1” level. A high level of total bilirubin at three months post Kasai is an indicator of a failing Kasai, witnessed with a significantly increased number of the “High HMGB1” patients resulting in liver transplants within the first two years.

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

Timchenko is a professor in the Division of Pediatric General and Thoracic Surgery at Cincinnati Children's and the UC Department of Surgery. He is also the head of Liver Tumor Biology for the Liver Tumor Program. His lab investigates mechanisms of 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. 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 Tiao and Bondoc within the division; Geller, from the Division of Oncology; Gupta, from the Division of Pathology; and other members of the Liver Tumor Program, 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. 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. 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. 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 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. Timchenko also found that the inhibition of cdk4 prevents / reverses early steps of NAFLD in animal models. Recent investigations by 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, 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 Timchenko’s lab focus on the role of liver proliferation in pediatric fatty liver disease and mechanisms of this disease.