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. This investigation may be pivotal in the discovery of novel therapies to treat patients, and the importance of GPC3 protein cleavage in HB tumor growth and proliferation. His lab utilizes single-cell sequencing technology to explore tumor heterogeneity and define the characteristics of tumor driver cell clusters. 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, murine models are 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 work examining the impact of social determinants of health on pediatric injury and interventions alongside community partners to address these root causes led by Meera Kotagal, MD, MPH. This work received funding from two Place Outcomes Awards from Cincinnati Children’s and a grant from the Ohio Department of Public Safety. In addition, we engage in important work to better understand the impact of injury on acute stress for both the patient and family with a lens on health equity. 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 three partners within the U.S. and maintains a partnership with a hospital in Poland which became 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. The impact of this program is far-reaching with over 1,000 homes with our home safety program and a presence in all 50 states and the Dominican Republic. Toyota provides generous funding for this important work.

Jason Frischer, MD

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

In November 2020, Frischer and the Colorectal Center team, in conjunction with the Pediatric Colorectal and Pelvic Reconstruction Consortium (PCPLC), led a two-day virtual (surgical, clinical, and scientific) seminar, with dozens of expert presenters, and hundreds of participants. Program topics included anorectal malformations, Hirschsprung disease, bowel management, gynecology, GI motility, and urology.

Conference objectives were ambitious and multifaceted.

• To utilize new innovations and apply evidence-based practices to the care of pediatric colorectal, GI, and gynecological patients.
• To apply standard-of-care practices by recognizing, supporting, and evaluating multidisciplinary care needs of pediatric colorectal, GI, and gynecological patients throughout their lifespans.
• To examine care practices and participate in innovative thinking with colleagues at the conference and at their own points of care.
• To develop a pediatric colorectal bowel management program.

Frischer and the Colorectal Center team studied the impact of radiology imaging on the clinical treatment plans for Bowel Management Program patients. The team captured and compiled data from every cohort since January 2021. Providers develop a plan based on medical history, clinical symptoms, daily bowel movement logs, medication, enemas, diet, and more independent from and prior to viewing radiology imaging. In doing so, the team is identifying where there are opportunities to reduce and individualize radiology imaging.

Providers are identifying a subset of good candidates and offering them a low-radiation alternative to the traditional program with fewer x-rays. With the traditional program involving daily abdominal x-rays over the course of six days, and often a water-soluble contrast enema, the appointments, cost, radiation exposure, and demands of real-time imaging results can decrease accessibility to the expertise of the Colorectal Center and decrease the ability to deliver care remotely. Preliminary results show promising signs for research-validated program innovations. Patients and families involved in the low-radiation program receive evaluations at specified intervals over time using severity score and quality of life measurements to ensure outcomes are comparably high.

Michael Helmrath, MD

Helmrath focuses his career on complex gastrointestinal diseases. He actively leads multidisciplinary clinical, translational, and basic science programs. He currently serves as the director of Surgical Research for Cincinnati Children’s. Helmrath currently oversees extramural, translational, and basic science studies focused on intestinal failure, obesity and type 2 diabetes, esophageal atresia, Hirschprung’s 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 disease mechanisms and 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. He serves as co-principal investigator with Meg Zeller, PhD, from the Division of Behavioral Medicine and Clinical Psychology, on the NIH-NIDDK funded project, “Adolescent Bariatric Surgery: Weight and Psychosocial Risk in Young Adulthood.”

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 how we can reduce the associated inequities. 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 the social determinants of health at a neighborhood level that underlie and drive pediatric injury in the Cincinnati region and State of Ohio. The work will help us understand the broader contextual factors driving who gets injured and how severe those injuries are. Using the findings from this analysis, Kotagal is working in partnership with community members and the injury prevention team at Comprehensive Children's Injury Center, as well as the All Children Thrive Network, to reduce pediatric injury in one neighborhood with disproportionately high rates of pediatric injury. Kotagal serves as the lead for the Trauma Services team within the Cincinnati Children's Health Equity Network (HEN), which focuses on improving patient care equity across the institution. The Trauma HEN team works to improve the transition from hospital to home for high-risk patients and to reduce both patient and family stress through a bundle of discharge-related interventions. Future research will focus on the family experience from hospital to home after injury and how to improve both patient and family stress, overall experience, and patient outcomes for all patients.

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), 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. 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 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 at the Ann & Robert H. Lurie Children's Hospital in Chicago, they use 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. This group uses 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 studying the origin and presence of intrauterine growth restriction in these fetuses with gastroschisis in collaboration with Mounira Habli, MD.

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 focusing 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 Gupta to discover novel strategies for prevention and treatment of liver cancer.

Gregory Tiao, MD

Tiao is the head 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 Liver Tumor Committee. Tiao’s lab, including research assistants Bryan Donnelly and Haley Temple, continues work on the pathogenesis of biliary atresia through an ongoing 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 cholangiocytes and dendritic cells governing intracellular trafficking of the virus resulting in activation of an innate immune response.

Mechanistic studies demonstrated high mobility group box-1 protein (HMGB1) release from both mouse and human cholangiocytes was dependent on the Rhesus rotavirus (RRV) VP4 protein. Analysis of human protein array data collected from biliary atresia patients at time of Kasai identified a subpopulation (28% of the cohort) that had high serum levels of HMGB1. At two-year follow-up, only 33% of the high HMGB1 group survived with their native liver, significantly lower than the 53% in the low HMGB1 BA group. A recently published manuscript in Hepatology entitled “HMGB1 release by cholangiocytes governs biliary atresia pathogenesis and correlates with increases in afflicted infants” reported these findings.

Generation of multiple novel rotavirus strains deficient in their ability to bind to individual cellular receptors demonstrated the release of HMGB1 associates with the ability to bind to the heat shock cognate 70 protein (Hsc70) on the surface of cells. Cholangiocytes infected with other viruses isolated from biliary atresia patients (Reovirus, CMV) were able to induce HMGB1 release illustrating a potential common pathway for disease initiation. Recently the research team submitted a manuscript detailing these findings for publication.

Tiao and 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 worldwide.

Nikolai Timchenko, PhD

Timchenko is a professor in the Division of Pediatric General and Thoracic Surgery at Cincinnati Children's and UC Department of Surgery. He is also 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 investigation; however, researchers do not know a great deal 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, James Geller, MD, from the Division of Oncology, Anita Gupta, MD, 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.

During the last seven years, Timchenko's lab collected and investigated specimens from patients with pediatric liver cancers using procedures which prevent the loss of protein modifications and degradation. This approach allowed examination of critical pathways in liver cancer previously missed due to insufficient protection during the collection of samples. The most important discovery with these HBL tumor samples is the identification of human genomic regions that activate multiple oncogenes in pediatric liver cancer. These DNA regions are cancer-enhancer genomic regions or aggressive liver cancer domains (CEGRs/ALCDs). Timchenko’s recent paper in Hepatology showed that, in aggressive HBL, the ph-S6-p53-PARP1 complexes activate CEGRs/ALCDs-containing oncogenes. He found that inhibition of PARP1 activity in patient-derived xenografts (PDXs) inhibits tumor growth. Search of the giant human DNA-Seq datasets (over 11,000 ChIP-Seq datasets) identified a β-catenin pathway that might activate CEGRs/ALCDs-containing oncogenes via direct binding of β-catenin-TCF4 complexes to CEGRs/ALCDs-dependent oncogenes. Timchenko is currently investigating if activation of β-catenin-TCF4-CEGRs/ALCDs pathway occurs in aggressive HBL and contributes to the aggressive features of HBL including lung metastases.

Timchenko is also working with epigenetic regulation of pediatric liver cancer. De-differentiation of hepatocytes into cancer cells is a first step of development of liver cancer. Timchenko recently published a paper showing the de-differentiation of hepatocytes involves repression of markers of hepatocytes and the increase of liver proliferation. Analyses of a fresh bio-bank of specimens from HBL patients showed that a significant portion of the HBL patients have increased levels of an oncogenic de-ph-S190-C/EBPα, SP5, and HDAC1 compared to amounts of these proteins in adjacent regions. Timchenko found creation of oncogenic de-ph-S190-C/EBPα in aggressive HBL by PP2A phosphatase, which increased within the nucleus and de-phosphorylates C/EBPα at Ser190. C/EBPα-HDAC1 and Sp5-HDAC1 complexes are abundant in hepatocytes which de-differentiate into cancer cells. Studies in HBL cells revealed that C/EBPα-HDAC1 and Sp5-HDAC1 complexes reduce markers of hepatocytes and p21 via repression of their promoters. Pharmacological inhibition of C/EBPα-HDAC1 and Sp5-HDAC1 complexes by SAHA and siRNA-mediated inhibition of HDAC1 increases expression of hepatocyte markers, p21, and inhibits proliferation of cancer cells.

Timchenko’s lab showed that development of another liver cancer, fibrolamellar carcinoma (FLC) also involves the activation of CEGRs/ALCDs oncogenes. The underlying molecular mechanisms associate with FLC-specific mutation that generates fusion oncoprotein DNAJB1-PKAc. Timchenko found that DNAJB1-PKAc phosphorylates β-catenin at Ser675 leading to increase of β-catenin-TCF4 complexes and to activation of CEGRs/ALCDs containing collagens and oncogenes.

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 found 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. 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.