Browsing by Author "Department of Pediatrics, School of Medicine"
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Item Amelioration of type 1 diabetes following treatment of non-obese diabetic mice with INGAP and lisofylline(SciRes, 2012-05-01) Tersey, Sarah A.; Carter, Jeffery D.; Rosenberg, Lawrence; Taylor-Fishwick, David A.; Mirmira, Raghavendra G.; Nadler, Jerry L.; Department of Pediatrics, School of MedicineType 1 diabetes mellitus results from the autoimmune and inflammatory destruction of insulin-producing islet β cells, rendering individuals devoid of insulin production. Recent studies suggest that combination therapies consisting of anti-inflammatory agents and islet growth-promoting factors have the potential to cause sustained recovery of β cell mass, leading to amelioration or reversal of type 1 diabetes in mouse models. In this study, we hypothesized that the combination of the anti-inflammatory agent lisofylline (LSF) with an active peptide fragment of islet neogenesis associated protein (INGAP peptide) would lead to remission of type 1 diabetes in the non-obese diabetic (NOD) mouse. We treated groups of spontaneously diabetic NOD mice with combinations of LSF, INGAP peptide, or control saline parenterally for up to 6 weeks. Our results demonstrate that the mice receiving combined treatment with LSF and INGAP peptide exhibited partial remission of diabetes with increased plasma insulin levels. Histologic assessment of pancreata in mice receiving combined therapy revealed the presence of islet insulin staining, increased β cell replication, and evidence of Pdx1-positivity in ductal cells. By contrast, diabetic animals showed severe insulitis with no detectible insulin or Pdx1 staining. We conclude that the novel combination treatment with LSF and INGAP peptide has the potential to ameliorate hyperglycemia in the setting of established type 1 diabetes via the recovery of endogenous β cells and warrant further studies.Item APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing(Wiley, 2017-12) Shah, Fenil; Goossens, Emery; Atallah, Nadia M.; Grimard, Michelle; Kelley, Mark R.; Fishel, Melissa L.; Department of Pediatrics, School of MedicineApurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1-knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single-cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial-related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT-PCR. Testing additional patient-derived pancreatic cancer cells reveals particular genes (ITGA1, TNFAIP2, COMMD7, RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox-specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis-driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.Item Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity(Oxford University Press, 2016-05-01) Zhan, Hong; Aizawa, Kenichi; Sun, Junqing; Tomida, Shota; Otsu, Kinya; Conway, Simon J.; Mckinnon, Peter J.; Manabe, Ichiro; Komuro, Issei; Miyagawa, Kiyoshi; Nagai, Ryozo; Suzuki, Toru; Department of Pediatrics, School of MedicineAIMS: Doxorubicin (Dox) is a potent anticancer agent that is widely used in the treatment of a variety of cancers, but its usage is limited by cumulative dose-dependent cardiotoxicity mainly due to oxidative damage. Ataxia telangiectasia mutated (ATM) kinase is thought to play a role in mediating the actions of oxidative stress. Here, we show that ATM in cardiac fibroblasts is essential for Dox-induced cardiotoxicity. METHODS AND RESULTS: ATM knockout mice showed attenuated Dox-induced cardiotoxic effects (e.g. cardiac dysfunction, apoptosis, and mortality). As ATM was expressed and activated predominantly in cardiac fibroblasts, fibroblast-specific Atm-deleted mice (Atm(fl/fl);Postn-Cre) were generated to address cell type-specific effects, which showed that the fibroblast is the key lineage mediating Dox-induced cardiotoxicity through ATM. Mechanistically, ATM activated the Fas ligand, which subsequently regulated apoptosis in cardiomyocytes at later stages. Therapeutically, a potent and selective inhibitor of ATM, KU55933, when administered systemically was able to prevent Dox-induced cardiotoxicity. CONCLUSION: ATM-regulated effects within cardiac fibroblasts are pivotal in Dox-induced cardiotoxicity, and antagonism of ATM and its functions may have potential therapeutic implications.Item The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease(Elsevier, 2017-02) Cooke, Kenneth R.; Luznik, Leo; Sarantopoulos, Stefanie; Hakim, Frances T.; Jagasia, Madan; Fowler, Daniel H.; van den Brink, Marcel R. M.; Hansen, John A.; Parkman, Robertson; Miklos, David B.; Martin, Paul J.; Paczesny, Sophie; Vogelsang, Georgia; Pavletic, Steven; Ritz, Jerome; Schultz, Kirk R.; Blazar, Bruce R.; Department of Pediatrics, School of MedicineChronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: • Summarize the current state of the science regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps. • Develop working hypotheses/overriding concepts for chronic GVHD development. • Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies. • Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.Item Contraception Options and Provision to Adolescents(2017-10) Robbins, Cynthia L.; Ott, Mary A.; Department of Pediatrics, School of MedicineAdolescent pregnancy is a significant cause of global morbidity and mortality. Adolescents who become pregnancy have lower educational attainment, are more likely to live in poverty, and have lower wellbeing. Increasing access to hormonal contraceptives and long acting reversible contraception is highly effective in reducing adolescent pregnancies. This narrative review covers key aspects of the provision of contraception to adolescents, including confidentiality, counseling, and data supporting expanded access to adolescents. We provide information for pediatric providers to start adolescent patients on contraceptives, including a detailed description of each method, including effectiveness, use, starting, side effects and benefits. Tools for counseling and prescribing are provided.Item Current opinions regarding care of the mature pediatric urology patient(Elsevier, 2015-10) Szymanski, Konrad M.; Misseri, Rosalia; Whittam, Benjamin; Large, Tim; Cain, Mark P.; Department of Pediatrics, School of MedicineIntroduction With continued improvements in pediatric urology care of patients with complex congenital genitourinary conditions, many survive into adulthood. This fact has created a challenging situation of transitioning from pediatric to adult care. Establishing long-term follow-up with appropriate specialists is a critical part of a successful transition to adulthood for this population. Objective This study sought to elucidate current practices and opinions regarding the management of adult complex genitourinary patients by pediatric urologists, in order to determine if a consensus for adult care exists. Study design An anonymous, 15-question online survey was created to address practice patterns and opinions regarding the transition of care of complex genitourinary patients. An invitation to participate was distributed via email to 200 pediatric urologists who were members of the American Urological Association. Complex genitourinary patients were defined broadly as those with a history of: spina bifida, bladder exstrophy, cloacal exstrophy, cloacal anomalies, posterior urethral valves or disorders of sex development. Fisher's exact test was used for analysis. Results The response rate was 31.0% (62/200). Two-thirds (67.7%) cared for adults with complex genitourinary conditions. Overall, 51.6% of pediatric urologists felt that general urologists best follow adult patients, but only 6.5% recommended this for patients with prior complex genitourinary reconstruction (P < 0.001). Instead, the majority (80.6%) felt that a pediatric or adult urologist with an interest and training in adolescent/transitional urology who routinely performs such procedures would provide optimal care. Follow-up by a primary care physician alone was not recommended. Recommendations did not change if patients had developmental delay or lived independently (P = 0.47 and P = 0.72, respectively). Overall, 69.4% would refer mature complex genitourinary patients to a urologist with interest and training in adolescent/transitional urology, if one was available. However, only 45.2% had such an individual available in their practice (P < 0.001). Discussion In the present study, the opinions of pediatric urologists regarding optimal providers of long-term follow-up for mature complex genitourinary patients were presented. While the results may not represent the views of the entire pediatric urology community, responses from motivated individuals with a particular interest in transition care may be especially valuable. Although the present study did not outline a mechanism for improving transitional care, it offered valuable information on prevailing opinions in this area. Finally, the opinions of mostly North American Pediatric Urologists were presented, which may not apply to other healthcare settings. Conclusions Pediatric urologists appeared to be virtually unanimous in recommending that urologists provide the most appropriate long-term follow-up of patients with congenital genitourinary conditions. Specifically, 80% recommended that patients with prior complex surgical reconstruction be followed by a urologist with specific interest, training and experience in the area of transitional urology. The data suggest that this may be an unmet need of these specialists and may signify the need for specific training in the care of such patients.Item Depressive symptoms are associated with fasting insulin resistance in obese youth(Wiley Online Library, 2014-10) Hannon, Tamara S.; Li, Zhuokai; Tu, Wanzhu; Humber, Jordan N.; Carroll, Aaron E.; Lagges, Ann M.; Gupta, Sandeep; Department of Pediatrics, School of MedicineBACKGROUND: In adults, depressive symptoms are positively associated with insulin resistance. OBJECTIVE: To determine whether an association exists between depressive symptoms and markers of insulin resistance in youth. METHODS: This study used a retrospective review of data from an obesity clinic. We evaluated the association between depressive symptoms (Children's Depression Inventory, CDI) and fasting insulin and homeostatic model assessment-insulin resistance (HOMA-IR) in obese youth (n = 207, age 10-18 years). Individuals with lower vs. higher CDI T-scores (<65 vs. ≥65) were compared; this cut-point is accepted as indicating the possibility of clinical depression. Multiple linear regression was used to evaluate relationships between CDI T-scores and insulin resistance. RESULTS: Fasting insulin and HOMA-IR values were 40% higher in patients with higher CDI T-scores (P = 0.04). After accounting for gender, race, age and body mass index, CDI T-score remained associated with HOMA-IR, although the strength of the association was small (b = 0.007, P = 0.049). CONCLUSIONS: Relationships between depressive symptoms and insulin resistance should be considered when evaluating obese youth.Item Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation(Elsevier, 2017-02) Farrell, Philip M.; White, Terry B.; Ren, Clement L.; Hempstead, Sarah E.; Accurso, Frank; Derichs, Nico; Howenstine, Michelle; McColley, Susanna A.; Rock, Michael; Rosenfeld, Margaret; Sermet-Gaudelus, Isabelle; Southern, Kevin W.; Marshall, Bruce C.; Sosnay, Patrick R.; Department of Pediatrics, School of MedicineObjective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.Item Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes(American Diabetes Association, 2015-11) Fisher, Marisa M.; Watkins, Renecia A.; Blum, Janice; Evans-Molina, Carmella; Chalasani, Naga; DiMeglio, Linda A.; Mather, Kieren J.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Department of Pediatrics, School of MedicineElevated ratios of circulating unmethylated to methylated preproinsulin (INS) DNA have been suggested to reflect β-cell death in type 1 diabetes (T1D). We tested the hypothesis that absolute levels (rather than ratios) of unmethylated and methylated INS DNA differ between subjects with new-onset T1D and control subjects and assessed longitudinal changes in these parameters. We used droplet digital PCR to measure levels of unmethylated and methylated INS DNA in serum from subjects at T1D onset and at 8 weeks and 1 year post-onset. Compared with control subjects, levels of both unmethylated and methylated INS DNA were elevated at T1D onset. At 8 weeks post-onset, methylated INS DNA remained elevated, but unmethylated INS DNA fell. At 1 year postonset, both unmethylated and methylated INS DNA returned to control levels. Subjects with obesity, type 2 diabetes, and autoimmune hepatitis exhibited lower levels of unmethylated and methylated INS compared with subjects with T1D at onset and no differences compared with control subjects. Our study shows that elevations in both unmethylated and methylated INS DNA occurs in new-onset T1D and that levels of these DNA species change during T1D evolution. Our work emphasizes the need to consider absolute levels of differentially methylated DNA species as potential biomarkers of disease.Item Endangered academia: preserving the pediatric surgeon scientist(Elsevier, 2017-07) Markel, Troy A.; Valsangkar, Nakul P.; Bell, Teresa M.; Kiel, Brandon A.; Zimmers, Teresa A.; Koniaris, Leonidas G.; Department of Pediatrics, School of MedicineBackground Pediatric surgery is one of the most difficult surgical fellowships to obtain. It requires stellar academic credentials and, often, dedicated time pursuing research. It is unknown, however, if pediatric surgeons maintain high academic output as faculty members. We hypothesized that the majority of pediatric surgeons do not pursue robust research activities as faculty, and therefore, over time, their academic productivity decreases. Methods Numbers of publications, citations, H-index, and NIH funding rates were determined for 4354 surgical faculty at the top-55 NIH based departments of surgery using websites, Scopus, NIH RePORTER, and Grantome. Continuous variables were compared with ANOVA and post-hoc Bonferroni; categorical variables by χ2 test. p < 0.05 was significant. Results In this dataset, 321 pediatric surgery (PS) faculty represented 7.4% of the cohort. Among PS faculty, 31% were assistant professors, 24% associate professors, 31% full professors and 13% had no academic rank. PS faculty had significantly more publications, a higher H index, and more high level NIH funding early in their careers at the assistant professor level compared to general surgeons. PS faculty at the associate professor level had equivalent high level NIH funding, but lower recentness and academic power compared to general surgeons. Professors of PS rebounded slightly, with only observed deficiencies in number of citations compared to general surgeons. Conclusions PS faculty in assistant professor ranks has higher scholarly productivity compared to equivalently ranked general surgeons. Despite some mild academic setbacks in midcareer, pediatric surgeons are able to maintain similar academic productivity to their general surgery colleagues by the time they are full professors. Level of evidence 2.