The Division of General Pediatric Surgery provides investigators an exciting environment for scholarly research activities of the highest quality. Through these resources, both new and established investigators can expand their research capabilities in pursuit of greater knowledge about pediatric surgery.
The Pediatric Surgical Research Lab Meeting is held in the Chung Lab Conference Room D-4132 MCN from 12:00 until 1:30 p.m. the third Wednesday of every month. Lunch is not provided, but you may bring your own.
Neuroblastoma Center of Excellence
Dai H. Chung, M.D.
Cancer is the second leading cause of deaths in children younger than 15. Among pediatric cancers, neuroblastoma is the most common extra-cranial solid tumor, accounting for nearly 10 percent of all childhood cancers. Annually, approximately 700 new cases occur in the United States. Nearly half of all cases appear in toddlers under age two.
Despite remarkable recent advances in pediatric cancer therapy, the overall prognosis for patients with advanced-stage neuroblastoma remains dismal, with a mortality for all tumor stages at 50 percent. Therefore, it is imperative to discern the critical cellular pathways linked with their aggressive tumor behavior.
Gastrin-releasing peptide (GRP), the mammalian equivalent of bombesin (BBS), is a gut/neuropeptide that stimulates the growth of a number of normal and neoplastic tissues through an autocrine, paracrine, or endocrine mechanisms, including normal gastrointestinal tract mucosa as well as various neoplastic tissues such as pancreatic cancer, colon cancer, and small cell lung cancer. We have previously shown that GRPR expression was increased in undifferentiated neuroblastomas, and GRP, acting through GRPR, triggers cell division in an autocrine/paracrine manner. In addition, we have identified the phosphatidylinositol 3-kinase (PI3K) pathway as an emergent critical signaling mechanism of GRPR-mediated neuroblastoma growth.
The major focus of our laboratory is to determine GRP/GRPR as an important novel therapeutic target in the treatment of neuroblastoma. Our published studies have shown important roles for the GRP-mediated PI3K/Akt pathway in the process of neuroblastoma growth and metastasis. The ongoing studies are logical extensions of previous findings and are designed to discern molecular mechanisms and signaling events regulating the process of GRP-induced neuroblastoma progression. We will also identify a novel importance of determining GRPR expression in clinically significant ‘high-risk' patients, as defined by the COG criteria, for designing clinical treatment protocols. Finally, our studies will enhance the knowledge of hormone-responsive cancer pathogenesis and help clarify the complex signaling pathways involved.
To date, there have been several pre-clinical new investigational drug trials using GRPR antagonists for a few select adult cancers. Therefore, our promising data could allow us to introduce a pre-clinical trial to target GRPR in ‘high-risk' patients with metastatic, refractory neuroblastomas and potentially lead to the development of novel therapy as adjuvant treatment for this devastating disease with high mortality rate in infants and children.
Rapidly evolving communication technologies, such as the internet and social media, offer patients and families powerful tools for communicating with healthcare institutions and managing their health. Dr. Jackson's research in biomedical informatics focuses on using such technologies to empower patients and families to take an active role in their health care. Her work has studied the usage of MyHealthAtVanderbilt, a web-based patient portal that allows patients and families seen at the Vanderbilt University Medical Center to interact with the healthcare system.
MyHealthAtVanderbilt offers diverse functions, including secure messaging between patients and healthcare providers. Dr. Jackson's work has shown that actual medical care is delivered through the portal messaging. For example, new problems are identified, and referrals are made or medications are adjusted.
Her laboratory has identified ethnic and racial disparities in use of the messaging function, and thus, disparities in access to care that may be created by patient portal technologies. Ongoing research projects seek to identify and address the causes of these disparities. Other projects are evaluating the level of care delivered through the messaging function and investigating whether messaging interactions constitute billable services.
Dr. Jackson's group has also developed self-management tools for MyHealthAtVanderbilt. One tool allows patients to set and track health-related goals. It may serve as the basis of managing a wide variety of chronic health conditions that are treated with behavioral modifications. This tool is currently being evaluated in a randomized trial to address obesity in an employee wellness program.
The role of CITED-1 in the development of embryonal tumors
Wilms' tumor, or nephroblastoma, is the most common renal malignancy of childhood. It is thought to arise from alterations in the coordinated differentiation of nephronic progenitor cells within the embryonic kidney. In an attempt to uncover factors that regulate the mesenchymal-to-epithelial transition of nephronic progenitor cells, we have identified unique expression of the transcriptional co-factor, CITED1, which is restricted to the undifferentiated metanephric mesenchyme of the embryonic kidney. In studies to evaluate its expression domain and functional role in nephronic patterning, we have shown that CITED1 downregulation occurs during epithelial transition, and that its overexpression in the nephronic progenitor cell population, the condensed metanephric mesenchyme (CM), blocks normal epithelial differentiation and nephronic patterning.
Despite normally being undetected in the postnatal human kidney, we showed in recent studies that CITED1 is expressed consistently in, and specifically appears to be a marker of, undifferentiated blastemal compartments of both experimental rat and human Wilms' tumors. We showed further that CITED1 is a marker of human Wilms' tumor pathogenicity, as the highest content of CITED1 protein is isolated from primary tumors of children presenting with disseminated Stage IV disease. Therefore CITED1-dependent transcriptional activation in Wilms' tumor represents a potential target for differentiation therapies.
An unexpected finding emanating from these characterization studies is that CITED1 expression in embryonic kidneys is restricted predominantly to the cytosolic compartment of the CM cells, whereas, in both rat and human Wilms' tumors, CITED1 is richly detected within the nuclear compartment of malignant blastema. We have previously shown that CITED1 contains a strong Nuclear Export Signal (NES) within its C-terminal transactivation domain. The mixed nuclear and cytoplasmic distribution of CITED1 in Wilms' tumors is consistent with loss of NES function, but how this mechanism is perturbed in malignant cells remains unknown. Our principle aims in these proposed studies is to test the functional and pathogenic significance of restricting CITED1 to the nucleus of Wilms' tumor cells and to identify the mechanism(s) by which CITED1 is enriched in the nuclear compartment of Wilms' tumor cells.
Molecular analysis of racial disparities in Wilms' tumor
We are conducting a unique study designed to explore the biological basis for ethnic variations in the development and progression of Wilms' tumor, a lethal childhood kidney cancer. Several epidemiological studies have shown that children of black African ancestry carry the highest risk to develop Wilms' tumor when compared with all other ethnic groups regardless of country citizenship, which suggests a different biology more than insufficient access to adequate therapy. However, no analyses examining the molecular or genetic etiology for these different incidence rates among ethnically diverse Wilms' tumor patients have been reported.
This study principally aims to identify novel and ethnic-specific targets in the development of future Wilms' tumor therapies. To accomplish our study aims, I have secured the outstanding collaboration and support of the Mass Spectrometry Research Center at Vanderbilt and also the Vanderbilt Institute for Global Health (VIGH). The initial phase of our studies will apply a MALDI-TOF IMS analysis of a training set of Wilms' tumor specimens available through Vanderbilt and then a test set of specimens already approved by and obtained from the Children's Oncology Group. Primary Wilms' tumor tissue and pre-therapy urine will be analyzed using mass spectrometry (MALDI-TOF) to establish a molecular fingerprint of protein expression specific to ethnicity. Taking advantage of the tremendous resources at the VIGH and the expertise within, we will subsequently explore molecular differences in the uniquely at-risk and underserved population of Wilms' tumor patients in Kenya. Results generated from Kenyan Wilms' tumor patients will be compared with specimens collected from the African-American and Caucasian-American children to establish a molecular signature specific to black African ancestry.
Defining successful pathways to scientific independence for Academic Surgeons
We will conduct a survey of academic surgeons to identify the most successful formula and pathway, along with any potential pitfalls, to scientific independence. The purpose of the study is to identify the most successful pathway(s) for aspiring academic surgeons to secure independent NIH-funding (primary endpoint, R01 award) and to identify any potential pitfalls for those who have been unsuccessful in that endeavor. Multiple secondary endpoints will be determined through the study as well.
Mutational analysis of hereditary pancreatitis pedigrees
Hereditary pancreatitis can be a life-long debilitating disorder that results in chronic abdominal pain (often severe), pancreatic exocrine insufficiency (i.e. abnormal fat and protein digestion) and insulin-dependent diabetes mellitus (endocrine insufficiency). This hereditary form of chronic relapsing pancreatitis has been associated with several activating mutations of the cationic trypsinogen gene. Normally, trypsinogen, an inactive precursor protein that upon enzymatic cleavage in the lumen of the bowel converts to an active state that then can carry out digestion of dietary proteins. However, if the trypsinogen gene is mutated and encodes for a spontaneously activating form of trypsinogen, then autoactivation of the pancreas may ensue before reaching the gut lumen. However, carriers of this mutation show variability in the extent and timing of symptoms with which they are affected.
Some harboring the mutation trypsinogen gene have no to very mild symptoms across a lifetime, whereas some present with profound complications of pancreatitis in early childhood. Seminal work completed roughly nine years ago at this institution characterized one specific mutation in several kindreds living within this region, which is a relatively robust area in this country for this genetic disorder. However, penetrance (i.e. the incidence and spectrum of symptoms) was not associated with this mutation. Several new mutations have been characterized since that study and new genetic sequencing techniques have been developed. We propose to reanalyze the precise compliment of mutations that our surrounding kindred harbor and to associate when and which symptoms present at different stages of development (infancy through adulthood). We aim to assign specific symptoms to specific gene mutations, or specific combinations of them, and to outline when such symptoms can be anticipated to arise across a lifetime. Such information will serve invaluable at counseling known pedigrees and may allow earlier intervention to alleviate pancreatic auto-destruction.
Harold Newt Lovvorn, III, M.D. Selected Publications
Original scientific articles most relevant to current proposals; selected from 27 peer-reviewed publications.
Assessment of body composition in children with cancer
This study will determine the changes in body composition that occur in children with cancer from diagnosis to end of therapy using bioelectrical impedance analysis (BIA). BIA is being compared to standard nutritional assessment measures (weight, serum albumin). The goal is to determine if a relationship exists between body composition determined by BIA and positive blood cultures, bone marrow recovery after chemotherapy, and outcome.
Assessment of body composition in children on ECMO
Extracorporeal membrane oxygenation (ECMO) is often a life-saving therapy in desperately ill patients. Many of these patients are fluid overloaded at the time of initiation of ECMO support. There is evidence this fluid imbalance is often exacerbated on ECMO and aggressive diuresis or hemofiltration are often employed to treat this. The duration of ECMO support is related to the fluid balance in the patient.
Weighing a patient on ECMO is not practical in that the tubing attached to the patient is critical and displacement can be catastrophic. Thus, the clinician relies on clinical assessment and intake and output data. It is not uncommon to under or over diurese patients, therefore a non-invasive method of determining fluid status is potentially quite useful. Bioelectrical impedance analysis (BIA) is such a method.
BIA has proven to be useful in a variety of fluid balance studies in patient's receiving hemodialysis. In addition to determining body water distribution, assessment of nutritional status can be determined. Bioelectrical impedance analysis (BIA) is a technique for measuring body composition in clinical settings. Bioelectrical impedance theory is based on a concept of the body as an ionic conductor, the resistance of which depends on length and cross-sectional area (volume), the ionic composition of the conducting volume, and the frequency of the driving current.
Bioelectrical impedance has two components: resistance of the tissues themselves; and reactance due to the capacitate effect of membranes, tissue interfaces, and nonionic tissues. Electrodes are placed on a wrist and an ankle and a mild (less than one milliamp) alternating electrical current is delivered. BIA is noninvasive, takes only a few minutes, and requires no active collaboration on the part of the patient.
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