Mass Spectrometry-NMR Lab

The Division of Pathology has been investing significantly towards the growth and development of a stronger metabolomics core service incorporating the expertise and resources of both the Mass Spectroscopy Facility, under the direction of Dr. Kenneth Setchell, PhD, and the nuclear magnetic resonance (NMR) service under the direction of Dr. Lindsay Romick-Rosendale, PhD. Metabolomics studies are highly complex, requiring sophisticated technology and resources to provide the Cincinnati Children's Hospital Medical Center investigators adequate technology for sensitive analysis and high throughput evaluation. The Mass Spectroscopy Facility has a longstanding, international recognized, successful track record for advancing the understanding of bile acid metabolism and characterizing the normal physiologic role bile acids play in the metabolism, as well as providing critical diagnostic testing for patients around the world with bile acid defects. This has now led to FDA approved clinical treatment of patients with these rare disorders as a result of decades of research involving Dr. Setchell in collaboration with Dr. James Heubi, MD, in the Division of Gastroenterology, Hepatology and Nutrition. Dr. Setchell continues his highly productive metabolomics core support including critical new scientific publications including the Journal of Science Translational Medicine on the impact of bile acid uptake on fatty liver disease, as well as other metabolic disorders including a recent publication in Nature, in collaboration with the Division of Human Genetics, on the underlying mechanism of tissue damage in Gaucher disease. Dr. Setchell’s Mass Spectroscopy Facility core service also provided important data for a recent publication in Nature, in collaboration with the Division of Experimental Hematology research group on stem cell microenvironment changes in leukemia. The Mass Spectroscopy Facility service is also providing critical support and expertise in collaboration with the efforts of Dr. Scott Wexelblatt, MD, in the Division of Neonatology, to address the explosive opioid crisis in this county, and, in particular, its role in neonatal abstinence syndrome. The mass spectroscopy lab provides critical and rapid drug testing confirmation for newborns throughout the entire Greater Cincinnati Area under the care of our neonatology group. In an effort to expand this service in the management and care of these newborns, Dr. Setchell and his group have developed new drug testing capabilities utilizing umbilical cord tissue, which will provide broader coverage in identifying affected newborns in a timely manner for our neonatologists confronted with the challenge on a daily basis in the newborn units. This type of testing, with the needed technical expertise and resources, is only available in a very limited number of labs throughout the country.

Dr. Romick-Rosendale has been a member of the Division of Pathology for the past few years, and is responsible for the establishment of the NMR lab as an additional resource for Cincinnati Children's investigators requiring full support in the metabolomics studies. During the past few years, Dr. Romick-Rosendale has provided analytical support based on NMR technology to a number investigators at Cincinnati Children's as well as other institutions, including the University of Cincinnati and the Cincinnati Zoo on metabolomics research. She provided critical analytical support to a large study directed by Dr. Louis Muglia, MD, PhD, in an effort to identify mother’s at risk for premature labor based on metabolic profiles. She evaluated more than 3,000 samples for the study with the goal of developing a reliable method for identifying these at risk patients. NMR technology support is also providing analysis of bone marrow transplant patients in collaboration with Dr. Stella Davies, MBBS, PhD, MRCP, in an effort to recognize and monitor bone marrow transplant patients at risk for a graft versus host disease, a deadly complication associated with bone marrow transplantation. The Cincinnati Zoo is also working closely with this core lab to perform a number of metabolic studies on endangered animals to improve birth rates, to identify metabolic disease in endangered animals, and to identify the development of cancer in some of these populations. This lab evaluated more than 2,000 samples in the past few years as a result of this collaboration for metabolomic studies. The near future for the metabolomics program in the division includes an effort to establish a lipidomics program as the next frontier to complete metabolomics studies at Cincinnati Children's. This will involve both mass spectroscopy and NMR based analyses, which will complement each other in providing this cutting edge technology for the advancement of metabolomics studies at Cincinnati Children's.

Leukemia Research

Dr. Mohammad Azam, PhD, a member of the Division of Pathology faculty, has a well-established program jointly supported by the Divisions of Pathology and Experimental Hematology studying drug resistance in various forms of chronic myeloid leukemia. Published recent work in this area are in Nature Medicine and Oncotarget. Chronic myeloid leukemia treatment with BCR-ABL inhibitors is often limited by the development of drug resistance. Therefore, as in other forms of cancer, therapy for human cancers is frequently not curative, and relapse occurs due to the continued presence of tumor cells recognized as minimal residual disease, many of which appear to have an intrinsic resistance to some forms of therapy. Studies, that Dr. Azam recently collaborated with other investigators at Cincinnati Children's Hospital Medical Center, have shown one small molecule compound, Bisindolylmaleimide IX inhibits DNA topoisomerase, generates DNA breaks, and induced cell cycle arrest and cell death. These studies found that this drug is highly effective in targeting cells positive for the BCR-ABL mutation. Dr. Azams's other related studies have recently shown that an oncogene (FOS), and a dual specificity phosphatase 1 (DUSP1), could be deleted, which suppressed tumor growth in BCR-ABL forms of chronic myeloid leukemia. Pharmacological inhibition of these genes eradicated minimal residual disease in multiple in vivo models including mice transplanted with patient derived primary CML cells. These studies demonstrate that the expression levels of these genes may determine the threshold of resistance to therapy in these tumor cells in a wide range of leukemias, and might represent a unifying tool for treating kinase driven cancers.