Browsing by Author "Renbarger, Jamie"
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Item A biomarker panel for risk of early respiratory failure following hematopoietic cell transplantation(American Society of Hematology, 2022) Rowan, Courtney M.; Smith, Lincoln; Sharron, Matthew P.; Loftis, Laura; Kudchadkar, Sapna; Duncan, Christine N.; Pike, Francis; Carpenter, Paul A.; Jacobsohn, David; Bollard, Catherine M.; Cruz, Conrad Russell Y.; Malatpure, Abhijeet; Farag, Sherif; Renbarger, Jamie; Little, Morgan R.; Gafken, Phillip R.; Krance, Robert A.; Cooke, Kenneth R.; Paczesny, Sophie; Pediatrics, School of MedicinePlasma biomarkers associated with respiratory failure (RF) following hematopoietic cell transplantation (HCT) have not been identified. Therefore, we aimed to validate early (7 and 14 days post-HCT) risk biomarkers for RF. Using tandem mass spectrometry, we compared plasma obtained at day 14 post-HCT from 15 patients with RF and 15 patients without RF. Six candidate proteins, from this discovery cohort or identified in the literature, were measured by enzyme-linked immunosorbent assay in day-7 and day-14 post-HCT samples from the training (n = 213) and validation (n = 119) cohorts. Cox proportional-hazard analyses with biomarkers dichotomized by Youden's index, as well as landmark analyses to determine the association between biomarkers and RF, were performed. Of the 6 markers, Stimulation-2 (ST2), WAP 4-disulfide core domain protein 2 (WFDC2), interleukin-6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), measured at day 14 post-HCT, had the most significant association with an increased risk for RF in the training cohort (ST2: hazard ratio [HR], 4.5, P = .004; WFDC2: HR, 4.2, P = .010; IL-6: HR, 6.9, P < .001; and TFNR1: HR, 6.1, P < .001) and in the validation cohort (ST2: HR, 23.2, P = .013; WFDC2: HR, 18.2, P = .019; IL-6: HR, 12.2, P = .014; and TFNR1: HR, 16.1, P = .001) after adjusting for the conditioning regimen. Using cause-specific landmark analyses, including days 7 and 14, high plasma levels of ST2, WFDC2, IL-6, and TNFR1 were associated with an increased HR for RF in the training and validation cohorts. These biomarkers were also predictive of mortality from RF. ST2, WFDC2, IL-6 and TNFR1 levels measured early posttransplantation improve risk stratification for RF and its related mortality.Item Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation.(Elsevier, 2015-10) Akil, Ayman; Zhang, Qing; Mumaw, Christen L.; Raiker, Nisha; Yu, Jeffrey; de Mendizabal, Nieves Velez; Haneline, Laura S.; Robertson, Kent A.; Skiles, Jodi; Diaz-Ricart, Maribel; Carreras, Enric; Renbarger, Jamie; Hanash, Samir; Bies, Robert R.; Paczesny, Sophie; Department of Pediatrics, IU School of MedicineReliable, non-invasive methods for diagnosing and prognosing sinusoidal obstruction syndrome (SOS) early after hematopoietic cell transplantation (HCT) are needed. We used a quantitative mass spectrometry-based proteomics approach to identify candidate biomarkers of SOS by comparing plasma pooled from 20 patients with and 20 patients without SOS. Of 494 proteins quantified, we selected six proteins [L-Ficolin, vascular-cell-adhesion-molecule-1 (VCAM1), tissue-inhibitor of metalloproteinase-1, von Willebrand factor, intercellular-adhesion-molecule-1, and CD97] based on a differential heavy/light isotope ratio of at least 2 fold, information from the literature, and immunoassay availability. Next, we evaluated the diagnostic potential of these six proteins and five selected from the literature [suppression of tumorigenicity-2 (ST2), angiopoietin-2 (ANG2), hyaluronic acid (HA), thrombomodulin, and plasminogen activator inhibitor-1] in samples from 80 patients. The results demonstrate that together ST2, ANG2,Item Exploring Exercise Outcomes, Preferences, and Barriers in Adolescent and Young Adult Cancer Survivors(2024-08) Sherman, Melissa Marie; Keith, NiCole R.; Kaushal, Navin; Naugle, Kelly; Renbarger, JamiePhysical activity (PA) improves physiology and cognition including Quality of Life (QoL), fatigue, depression, anxiety, and emotional well-being. Despite the positive effects of PA, adolescent, and young adult (AYA) cancer survivors (15-39 yrs.) do not meet the American College of Sports Medicine (ACSM) recommended PA guidelines to elicit positive health outcomes. AYA survivors may have unique physical and psychological experiences that impact motivation, barriers, and preferences for participation in PA. The overarching purpose of this dissertation is to better understand the outcomes, motivation, preferences, and barriers to exercise adherence when completing exercise and PA interventions among AYA survivors of cancer. This dissertation addresses this purpose through three distinct studies: AYA Cancer Survivors and One-on-One Exercise in an In-person setting, AYA Cancer Survivors and One-on-One Exercise in a Virtual Setting, and subsequent focus groups that utilized the participants from both virtual and in-person studies. Results indicated that the nature of cancer and cancer treatment, type of cancer, age at diagnosis, and experience within treatment (i.e. surgery, radiation, chemotherapy, stem cell transplants) varied significantly across AYA survivors of cancer. Despite the differences in experience, cancer-related fear and anxiety were common among participants but were offset by a sense of control and accountability experienced during the larger study. Working one-on-one with a wellness coach or exercise trainer provided participants with a sense of accountability and a sense of control that otherwise was missing post-cancer treatment and remission. The extra support is needed to help alleviate fears and anxiety and to promote accountability, acceptability, and adherence to exercise. A multi-disciplinary approach with wellness coaching and individualized PA guidance is suggested for future programming in this population group. While AYA survivors of cancer are an often understudied population, future research must target more racially and ethnically diverse groups to understand this group as a whole better.Item Glutathione-S-transferase P1 may predispose children to a decline in pulmonary function after stem cell transplant(Wiley, 2017-07) Stark, Julie; Renbarger, Jamie; Slaven, James; Yu, Zhangsheng; Then, Jenny; Skiles, Jodi; Davis, Stephanie; Pediatrics, School of MedicineRATIONALE: Pulmonary complications after hematopoietic stem cell transplant (SCT) are associated with increased mortality. Genetic markers for those at risk for pulmonary impairment post-SCT have not been widely investigated. METHODS: Forty-nine patients were retrospectively selected from a single institution's biorepository with linked clinical data. All subjects performed pre-SCT PFTs. Genotyping was conducted using the Infinium Exome-24 BeadChip. Four single nucleotide polymorphisms (SNPs) were selected (rs1800871, rs1695, rs1800629, rs12477314) and evaluated for association with PFT parameters as change over time from baseline. Associations between SNPs and PFT parameters were assessed and adjusted for the following confounding variables: age, gender, and race. RESULTS: Using the recessive genetic model, patients with one or two minor alleles for the glutathione S-transferase P1 (GSTP1) SNP rs1695 had a lower decline in FEV1 and FEF25-75 at 1-year post-SCT compared to patients who were homozygous for the ancestral allele (adjusted P-values <0.01 and 0.02, respectively). No other SNPs were significantly associated with other PFT parameters. CONCLUSIONS: Our findings suggest that GSTP1 genotype may be associated with lung function during the first year post-SCT. Identifying and investigating genes that predispose patients to pulmonary complications after SCT may allow for more personalized patient management based on pre-emptive genetic testing. The glutathione S-transferase gene merits further investigation.Item How Pediatric Hematologic and Oncologic Patients Experienced Virtual Learning During COVID-19: Importance of Amplifying the Family Voice for Informing Future Recommendations(Indiana University, 2020) Rose, Margaret; LaMotte, Julia; Todd, Hannah; Fraser, Greer; Fraser, Louise; Renbarger, Jamie; Romack, Donna; Sajdyk, Tammy; Pediatrics, School of MedicineItem Hypoxia-Inducible Factor-1α Regulates CD55 in Airway Epithelium(American Thoracic Society, 2016-12) Pandya, Pankita H.; Fisher, Amanda J.; Mickler, Elizabeth A.; Temm, Constance J.; Lipking, Kelsey P.; Gracon, Adam; Rothhaar, Katia; Sandusky, George E.; Murray, Mary; Pollok, Karen; Renbarger, Jamie; Blum, Janice S.; Lahm, Tim; Wilkes, David S.; Microbiology and Immunology, School of MedicineAirway epithelial CD55 down-regulation occurs in several hypoxia-associated pulmonary diseases, but the mechanism is unknown. Using in vivo and in vitro assays of pharmacologic inhibition and gene silencing, the current study investigated the role of hypoxia-inducible factor (HIF)-1α in regulating airway epithelial CD55 expression. Hypoxia down-regulated CD55 expression on small-airway epithelial cells in vitro, and in murine lungs in vivo; the latter was associated with local complement activation. Treatment with pharmacologic inhibition or silencing of HIF-1α during hypoxia-recovered CD55 expression in small-airway epithelial cells. HIF-1α overexpression or blockade, in vitro or in vivo, down-regulated CD55 expression. Collectively, these data show a key role for HIF-1α in regulating the expression of CD55 on airway epithelium.Item Identifying Genetic Variants in Adolescents With Oppositional Defiant Disorders and/or Conduct Disorders: A Brief Report(Wiley, 2016-08) Oruche, Ukamaka M.; Ross, Sydney E.; Carpenter, Janet S.; Renbarger, Jamie; Department of Nursing, School of NursingPROBLEM To add to diversity in our state biobank, we explored the feasibility of collecting genetic material from adolescents with oppositional defiant disorder (ODD) and/or conduct disorder (CD) and their family members. We also preliminarily explored genetic factors associated with ODD and/or CD by comparing participant data to 1000 Genome Project data on minor allele frequencies. METHODS Adolescents with ODD and/or CD and family members provided saliva samples for genetic testing. We evaluated five single-nucleotide polymorphisms (SNPs), respectively, in the dopamine receptor subtype D2, dopamine receptor subtype D3, dopamine beta-hydroxylase, dopamine transporter gene SLC6A3, and alpha-2-adrenergic receptor genes. Fisher's exact tests were used to examine differences in minor allele frequencies for each SNP. FINDINGS Thirty-one viable samples were genotyped from 15 affected adolescents and 16 unaffected family members; the 60% consent rate reflected high feasibility. Compared with the 1000 Genome Project frequencies, affected adolescents had higher frequencies of the genetic variant in the dopamine receptor subtype D2 (p = .05) and dopamine beta-hydroxylase (p = 0.03), but not of the other three SNPs examined. CONCLUSIONS Collecting genetic materials from an ethnically diverse sample of affected adolescents and their families is feasible. We offer practical suggestions to strengthen the integrity of future research studies.Item A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy(Springer, 2020-04-15) Verma, Parul; Devaraj, Jayachandran; Skiles, Jodi L.; Sajdyk, Tammy; Ho, Richard H.; Hutchinson, Raymond; Wells, Elizabeth; Li, Lang; Renbarger, Jamie; Cooper, Bruce; Ramkrishna, Doraiswami; Pediatrics, School of MedicineVincristine is a core chemotherapeutic drug administered to pediatric acute lymphoblastic leukemia patients. Despite its efficacy in treating leukemia, it can lead to severe peripheral neuropathy in a subgroup of the patients. Peripheral neuropathy is a debilitating and painful side-effect that can severely impact an individual’s quality of life. Currently, there are no established predictors of peripheral neuropathy incidence during the early stage of chemotherapeutic treatment. As a result, patients who are not susceptible to peripheral neuropathy may receive sub-therapeutic treatment due to an empirical upper cap on the dose, while others may experience severe neuropathy at the same dose. Contrary to previous genomics based approaches, we employed a metabolomics approach to identify small sets of metabolites that can be used to predict a patient’s susceptibility to peripheral neuropathy at different time points during the treatment. Using those identified metabolites, we developed a novel strategy to predict peripheral neuropathy and subsequently adjust the vincristine dose accordingly. In accordance with this novel strategy, we created a free user-friendly tool, VIPNp, for physicians to easily implement our prediction strategy. Our results showed that focusing on metabolites, which encompasses both genotypic and phenotypic variations, can enable early prediction of peripheral neuropathy in pediatric leukemia patients.Item Opportunities and challenges of proteomics in pediatric patients: circulating biomarkers after hematopoietic stem cell transplantation as a successful example(Wiley, 2014-12) Paczesny, Sophie; Duncan, Christine; Jacobsohn, David; Krance, Robert; Leung, Kathryn; Carpenter, Paul; Bollard, Catherine; Renbarger, Jamie; Cooke, Kenneth; Department of Medicine, IU School of MedicineBiomarkers have the potential to improve diagnosis and prognosis, facilitate-targeted treatment, and reduce health care costs. Thus, there is great hope that biomarkers will be integrated in all clinical decisions in the near future. A decade ago, the biomarker field was launched with great enthusiasm because MS revealed that blood contains a rich library of candidate biomarkers. However, biomarker research has not yet delivered on its promise due to several limitations: (i) improper sample handling and tracking as well as limited sample availability in the pediatric population, (ii) omission of appropriate controls in original study designs, (iii) lability and low abundance of interesting biomarkers in blood, and (iv) the inability to mechanistically tie biomarker presence to disease biology. These limitations as well as successful strategies to overcome them are discussed in this review. Several advances in biomarker discovery and validation have been made in hematopoietic stem cell transplantation, the current most effective tumor immunotherapy, and these could serve as examples for other conditions. This review provides fresh optimism that biomarkers clinically relevant in pediatrics are closer to being realized based on: (i) a uniform protocol for low-volume blood collection and preservation, (ii) inclusion of well-controlled independent cohorts, (iii) novel technologies and instrumentation with low analytical sensitivity, and (iv) integrated animal models for exploring potential biomarkers and targeted therapiesItem Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation(The American Society for Clinical Investigation, 2023-05-22) Han, Yan; Bidgoli, Alan; DePriest, Brittany P.; Méndez, Alejandra; Bijangi-Vishehsaraei, Khadijeh; Perez-Albuerne, Evelio D.; Krance, Robert A.; Renbarger, Jamie; Skiles, Jodi L.; Choi, Sung W.; Liu, Hao; Paczesny, Sophie; Biostatistics and Health Data Science, School of MedicineBACKGROUND: Currently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using 3 proteins: L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2). METHODS: Between 2017 and 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence on day 35 after HCT, and overall survival (OS) on day 100 after HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort. RESULTS: Combination of the 3 biomarkers measured on day 3 after HCT in the prospective cohort provided 80% (95% CI 55%–100%) sensitivity and 73% (95% CI 62%–83%) specificity for risk of SOS occurrence. Patients with low L-ficolin were 9 times (95% CI 3–32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95% CI 1.9–22.0) and 5.5 (95% CI 2.3–13.1) times more likely to develop SOS. These 3 markers also predicted worse day 100 OS — L-ficolin: HR, 10.0 (95% CI 2.2–45.1), P = 0.0002; HA: HR, 4.1 (95% CI 1.0–16.4), P = 0.031; and ST2: HR, 3.9 (95% CI 0.9–16.4), P = 0.04. CONCLUSION: L-ficolin, HA, and ST2 levels measured as early as 3 days after HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy.