Alexander Bondoc, MD

Dr. Alexander Bondoc, MD, is a new investigator in the Division of Pediatric General and Thoracic Surgery. Dr. Bondoc’s laboratory works in conjunction with Dr. Nikolai Timchenko's lab (https://www.cincinnatichildrens.org/bio/t/nikolai-timchenko) 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. Additionally, Dr. Bondoc’s laboratory generates patient derived xenografts (PDX) of human HBL and hepatocellular carcinoma (HCC) to augment understanding 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 selected for submission for a funding grant from the Chilldress 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 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. Toyota provides generous funding for this important work. 

Michael Helmrath, MD

Dr. 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 Hospital Medical Center. Dr. Helmrath currently oversees ongoing national, and international, clinical trials for intestinal failure and bariatric surgery. These studies include the GIFT’2 and TeenLabs. 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 receives continuously funding by multiple NIH awards. 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 associate 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

Dr. Todd Jenkins, PhD, MPH, is an associate professor in the Division of Pediatric General and Thoracic Surgery, and deputy 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 was recently awarded a UM1 from the National Institutes of Health, NIDDK, (https://www.niddk.nih.gov/) titled “Continuation of Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS), Biostatistics Research Center” in collaboration with Dr. Changchun Xie, PhD, associate professor of biostatistics, Department of Environmental Health, at the University of Cincinnati.

Helen Jones, PhD

Dr. 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. 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, 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 has 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 Dr. 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 Dr. Thaddeus Golos, PhD, at University of Wisconsin Madison and submitted a collaborative National Institutes of Health application.

In collaboration with Dr. James Cnota, MD, and the Heart Institute, the Jones lab has 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 in vitro human cell models and mouse models to investigate disturbances in the development and signaling of the heart-placenta axis throughout gestation.

Dr. Jones and her team furthered collaborations with Dr. Kasper Hoebe, PhD, in the Division of Immunobiology to study the role of maternal immune modulation of placental invasion with the submission of a collaborative NIH application. Dr. Jones maintained collaborations with Dr. Laura Woollett, UC Pathology, to study the effects of cholesterol on placental development and function, as well as collaborations with Drs. Louis Muglia, MD, PhD, and Michaela Pavlicev, PhD, in the Center for Prevention of Preterm Birth, to investigate placental involvement in preterm birth. These collaborations have been fruitful leading to both impactful publications, and two successful NIH grant applications. Dr. Jones has built on the collaboration with Dr. Shelley Ehrlich, MD, ScD, MPH, in the Division of Biostatistics and Epidemiology, to investigate the effects of environmental exposures on placental development, signaling and fetal programming resulting in several collaborative NIH applications.

Maxime Mahe, PhD

Dr. 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. Additionally, Dr. Mahe received the Athena Blackburn Research Scholar Award from the American Gastroenterology Association and a NIH K99DK110414 Career development award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Jaimie Nathan, MD

Dr. Jaimie Nathan, MD, surgical director of the Pancreas Care Center, and his team have established the total pancreatectomy and islet autotransplantation (TPIAT) program at Cincinnati Children’s Hospital Medical Center 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), which has 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 are initiating studies to investigate 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 Dr. Jose L. 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.

New Trends in Spina Bifida and Neural Tube Defects
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, Professor Chia-Ying Lin's Lab, and then translating these techniques for use in the human fetus. A new clinical trial is now comparing fetoscopic MMC repair in humans versus the standardized open fetal surgery approach. A MRI prenatal assessment is now 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 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
In CDH, they continue studies in animal models that indicate that early fetal tracheal occlusion may induce faster and better fetal lung growth. They described comparison of a novel CDH surgically induced model in rats with gene-expression to the teratogen nitrofen-induced CDH model in a collaborative study with Dr. Jeffrey Whitsett’s research group. This group is determining in rodents a new radiologic prenatal and postnatal biomarker by 3D lung assessment for better prognosis of pulmonary hypertension. In collaboration with Dr. Brian Varisco's lab, they are looking for the molecular pathways involved in the 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 associates 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 Dr. Mounira Habli, MD, and Dr. Helen Jones’ lab.

Soona Shin, PhD

Dr. 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. Nikolai Timchenko, Alexander Bondoc, and Anita Gupta, to discover novel strategies for prevention and treatment of liver cancer.

Gregory Tiao, MD

Dr. 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 Dr. Sujit Mohanty, along with research assistants Bryan Donnelly and Haley Temple, continues work on the pathogenesis of biliary atresia. Recently published data from his lab identified a novel cell binding site on rhesus rotavirus’s (RRV) VP4 protein. The amino acid sequence “SRL” (445-447) within VP4 protein binds to the heat shock cognate protein 70 (Hsc70) expressed on cholangiocytes membrane. A sequence search of the National Center for Biotechnology Information (NCBI) reveal that 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.

A second publication details an innovative reverse genetics system used to generate a mutant RRV with a single amino acid where altered arginine (R) in the “SRL” sequence becomes glycine (G). Cholangiocytes (biliary epithelial cells) infected with this mutant virus replicated to a significantly lower level when compared to wild-type RRV. Mice injected with this mutant RRV no longer develop murine biliary atresia. Currently they are generating a series of VP4 mutants with amino acid substitutions in other binding sites, and are studying their effects in disease pathogenesis.

Dr. Tiao along with Dr. 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 across the world.

Nikolai Timchenko, PhD

Dr. Nikolai Timchenko, PhD, is a professor in the Division of Pediatric General and Thoracic Surgery at Cincinnati Children's Hospital Medical Center 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 has 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. Gregory Tiao, MD, and Alex Bondoc, MD, from the Division of Pediatric General and Thoracic Surgery; Dr. James Geller, MD, from the Division of Oncology; and Dr. 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 and discovered 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 results 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 has found that this domain is under control of PARP1 protein and that aggressive hepatoblastoma utilizes PARP1-ALCD axis to elevate the mutant beta-catenin and NRF2 genes as well as many other oncogenes. Current studies focus on the generation of the patient-derived xenograft models (PDXs), and the development of drugs to inhibit classic and aggressive HBL by inhibiting corresponding FXR-Gank and PARP1-ALCD pathways. 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 of NAFLD. Recent investigations by Dr. Timchenko’s lab revealed 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 studies were recently published in two Cell Reports papers and in Aging Cell. These discoveries received extensive media coverage. Since cdk4 is a strong promoter of liver proliferation, current Dr. Timchenko’s studies focus of the role of proliferation in NAFLD.