Browsing by Author "Renbarger, Jamie L."
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Item An adolescent rat model of vincristine-induced peripheral neuropathy(Elsevier, 2021-11-11) Li, Ai-Ling; Crystal, Jonathon D.; Lai, Yvonne Y.; Sajdyk, Tammy J.; Renbarger, Jamie L.; Hohmann, Andrea G.; Pediatrics, School of MedicineChildhood acute lymphoblastic leukemia (ALL) is a significant clinical problem that can be effectively treated with vincristine, a vinca alkaloid-based chemotherapeutic agent. However, nearly all children receiving vincristine treatment develop vincristine-induced peripheral neuropathy (VIPN). The impact of adolescent vincristine treatment across the lifespan remains poorly understood. We, consequently, developed an adolescent rodent model of VIPN which can be utilized to study possible long term consequences of vincristine treatment in the developing rat. We also evaluated the therapeutic efficacy of voluntary exercise and potential impact of obesity as a genetic risk factor in this model on the development and maintenance of VIPN. Out of all the dosing regimens we evaluated, the most potent VIPN was produced by fifteen consecutive daily intraperitoneal (i.p.) vincristine injections at 100 µg/kg/day, throughout the critical period of adolescence from postnatal day 35 to 49. With this treatment, vincristine-treated animals developed hypersensitivity to mechanical and cold stimulation of the plantar hind paw surface, which outlasted the period of vincristine treatment and resolved within two weeks following the cessation of vincristine injection. By contrast, impairment in grip strength gain was delayed by vincristine treatment, emerging shortly following the termination of vincristine dosing, and persisted into early adulthood without diminishing. Interestingly, voluntary wheel running exercise prevented the development of vincristine-induced hypersensitivities to mechanical and cold stimulation. However, Zucker fa/fa obese animals did not exhibit higher risk of developing VIPN compared to lean rats. Our studies identify sensory and motor impairments produced by vincristine in adolescent animals and support the therapeutic efficacy of voluntary exercise for suppressing VIPN in developing rats.Item Assessment of Pediatric Chemotherapy-Induced Peripheral Neuropathy Using a New Patient-Reported Outcome Measure: The P-CIN(Sage, 2021) Smith, Ellen M. Lavoie; Kuisell, Clare; Kanzawa-Lee, Grace; Bridges, Celia M.; Cho, Youmin; Swets, Jenna; Renbarger, Jamie L.; Gilchrist, Laura S.; Medicine, School of MedicineBackground: Chemotherapy-induced peripheral neuropathy (CIPN) is commonly experienced by children receiving neurotoxic chemotherapy. No validated pediatric CIPN patient-reported outcome (PRO) measures exist. Purpose: To test sensitivity, internal consistency reliability, content and convergent validity, and feasibility of the Pediatric Chemotherapy-Induced Neuropathy (P-CIN), an electronic PRO measure for assessing CIPN in children who received neurotoxic chemotherapy. Method: Five experts evaluated content validity of the 14-item P-CIN. Children 5 to 17 years old with CIPN (N = 79) completed the P-CIN via tablet computer; a subset (n = 26) also underwent neurological examinations using the Pediatric-Modified Total Neuropathy Score. Following preliminary analyses, one item was deleted and three others modified. The revised P-CIN was retested with patients (n = 6) who also completed the Bruininks-Oseretsky Test of Motor Proficiency motor function assessment. Means, item response ranges, standard deviations, content validity indexes, Cronbach's alphas, and correlation coefficients were calculated. Results: Mean participant age was 11.25 (SD = 4.0) years. Most had acute leukemia (62.5%) and received vincristine (98.7%). Content validity index coefficients ranged from .80 to 1.0 (p = .05). For 9 of 14 items, responses ranged from 0 to 4 or 5; response ranges for toe numbness, pick up a coin, and three of four pain items were 0 to 3. After deleting one item, Cronbach's alpha coefficient was .83. P-CIN scores were strongly associated with Pediatric-Modified Total Neuropathy Score (r = .52, p < .01) and Bruininks-Oseretsky Test of Motor Proficiency (r = -.83, p = .04) scores. Sixty-eight percent of children 6 to 17 years old completed P-CIN independently. Discussion: Preliminary evidence suggests that the 13-item P-CIN is internally consistent, is valid, and can be completed independently by children ≥ 6 years. However, we recommend additional testing.Item Collection of human genomic DNA from neonates: a comparison between umbilical cord blood and buccal swabs(Elsevier, 2011-04) Lehmann, Amalia S.; Haas, David M.; McCormick, Catherine L.; Skaar, Todd C.; Renbarger, Jamie L.OBJECTIVE: To compare DNA yield from neonatal umbilical cord blood and buccal swab specimens. STUDY DESIGN: Umbilical cord blood was obtained at birth in a cohort of women enrolled in a preterm labor study. If cord blood was not obtained, neonatal buccal samples were obtained using the Oragene saliva kits. DNA was extracted from all samples using the QIAamp extraction kits. DNA concentration and yield were compared between umbilical cord blood and buccal swabs. RESULTS: DNA concentrations from umbilical cord blood (n = 35) was greater than that obtained from buccal swabs (n = 20) (total sample: 209.0 ± 110.7 ng/μL vs 6.9 ± 6.7 ng/μL respectively, P < .001; partial sample: n = 30 cord blood vs n = 11 buccal, 70.0 ± 51.4 ng/μL vs 11.3 ± 6.7 ng/μL, respectively, P < .001) and produced more total DNA (total sample: 116.5 ± 70.8 μg vs 4.2 ± 4.0 μg, P < .001; partial:14.0 ± 10.3 μg vs 1.1 ± 0.7 μg, respectively, P < .001). CONCLUSION: Buccal swabs yield less neonatal DNA than umbilical cord blood specimens.Item CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer(Wiley, 2018-03) Skiles, Jodi L.; Chiang, ChienWei; Li, Claire H.; Martin, Steve; Smith, Ellen L.; Olbara, Gilbert; Jones, David R.; Vik, Terry A.; Mostert, Saskia; Abbink, Floor; Kaspers, Gertjan J.; Li, Lang; Njuguna, Festus; Sajdyk, Tammy J.; Renbarger, Jamie L.; Pediatrics, School of MedicineBACKGROUND: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. PROCEDURE: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2 /dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. RESULTS: The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2 /l vs. 0.15 ± 0.011 hr·m2 /l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. CONCLUSION: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.Item Differential effects of hydrocortisone, prednisone, and dexamethasone on hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal hyperplasia(BioMed Central, 2016) Nebesio, Todd D.; Renbarger, Jamie L.; Nabhan, Zeina M.; Ross, Sydney E.; Slaven, James E.; Li, Lang; Walvoord, Emily C.; Eugster, Erica A.; Department of Pediatrics, IU School of MedicineBACKGROUND: Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. METHODS: Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. RESULTS: Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BMI. SNP analysis revealed significant associations between hormone concentrations, pharmacokinetic parameters, and variants in several glucocorticoid pathway genes (ABCB1, NR3C1, IP013, GLCCI1). CONCLUSIONS: DEX resulted in marked adrenal suppression suggesting that its potency relative to hydrocortisone and prednisone was underestimated. SNPs conferred significant differences in responses between subjects. Although preliminary, these pilot data suggest that incorporating pharmacogenetics has the potential to eventually lead to targeted therapy in children with CAH.Item Gene Co-Expression Networks Restructured Gene Fusion in Rhabdomyosarcoma Cancers(MDPI, 2019-08-30) Helm, Bryan R.; Zhan, Xiaohui; Pandya, Pankita H.; Murray, Mary E.; Pollok, Karen E.; Renbarger, Jamie L.; Ferguson, Michael J.; Han, Zhi; Ni, Dong; Zhang, Jie; Huang, Kun; Medicine, School of MedicineRhabdomyosarcoma is subclassified by the presence or absence of a recurrent chromosome translocation that fuses the FOXO1 and PAX3 or PAX7 genes. The fusion protein (FOXO1-PAX3/7) retains both binding domains and becomes a novel and potent transcriptional regulator in rhabdomyosarcoma subtypes. Many studies have characterized and integrated genomic, transcriptomic, and epigenomic differences among rhabdomyosarcoma subtypes that contain the FOXO1-PAX3/7 gene fusion and those that do not; however, few investigations have investigated how gene co-expression networks are altered by FOXO1-PAX3/7. Although transcriptional data offer insight into one level of functional regulation, gene co-expression networks have the potential to identify biological interactions and pathways that underpin oncogenesis and tumorigenicity. Thus, we examined gene co-expression networks for rhabdomyosarcoma that were FOXO1-PAX3 positive, FOXO1-PAX7 positive, or fusion negative. Gene co-expression networks were mined using local maximum Quasi-Clique Merger (lmQCM) and analyzed for co-expression differences among rhabdomyosarcoma subtypes. This analysis observed 41 co-expression modules that were shared between fusion negative and positive samples, of which 17/41 showed significant up- or down-regulation in respect to fusion status. Fusion positive and negative rhabdomyosarcoma showed differing modularity of co-expression networks with fusion negative (n = 109) having significantly more individual modules than fusion positive (n = 53). Subsequent analysis of gene co-expression networks for PAX3 and PAX7 type fusions observed 17/53 were differentially expressed between the two subtypes. Gene list enrichment analysis found that gene ontology terms were poorly matched with biological processes and molecular function for most co-expression modules identified in this study; however, co-expressed modules were frequently localized to cytobands on chromosomes 8 and 11. Overall, we observed substantial restructuring of co-expression networks relative to fusion status and fusion type in rhabdomyosarcoma and identified previously overlooked genes and pathways that may be targeted in this pernicious disease.Item The Immune System in Cancer Pathogenesis: Potential Therapeutic Approaches(Hindawi, 2016-12-26) Pandya, Pankita H.; Murrary, Mary E.; Pollok, Karen E.; Renbarger, Jamie L.; Department of Medicine, IU School of MedicineInterplay among immune activation and cancer pathogenesis provides the framework for a novel subspecialty known as immunooncology. In the rapidly evolving field of immunooncology, understanding the tumor-specific immune response enhances understanding of cancer resistance. This review highlights the fundamentals of incorporating precision medicine to discover new immune biomarkers and predictive signatures. Using a personalized approach may have a significant, positive impact on the use of oncolytics to better guide safer and more effective therapies.Item Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma(BMC, 2019-01-31) Cheng, Lijun; Pandya, Pankita H.; Liu, Enze; Chandra, Pooja; Wang, Limei; Murray, Mary E.; Carter, Jacquelyn; Ferguson, Michael; Saadatzadeh, Mohammad Reza; Bijangi-Visheshsaraei, Khadijeh; Marshall, Mark; Li, Lang; Pollok, Karen E.; Renbarger, Jamie L.; Pediatrics, School of MedicineBackground While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new therapies are urgently needed to improve survival and quality of life in pediatric patients with sarcomas. Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas. Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse. The objective of this study was to utilize publicly available data sets to identify potential predictive biomarkers of chemotherapeutic response in pediatric Osteosarcoma (OS), Rhabdomyosarcoma (RMS) and Ewing’s Sarcoma Family of Tumors (ESFTs) based on CNVs following chemotherapy (OS n = 117, RMS n = 64, ESFTs n = 25 tumor biopsies). Methods There were 206 CNV profiles derived from pediatric sarcoma biopsies collected from the public databases TARGET and NCBI-Gene Expression Omnibus (GEO). Through our comparative genomic analyses of OS, RMS, and ESFTs and 22,255 healthy individuals called from the Database of Genomic Variants (DGV), we identified CNVs (amplifications and deletions) pattern of genomic instability in these pediatric sarcomas. By integrating CNVs of Cancer Cell Line Encyclopedia (CCLE) identified in the pool of genes with drug-response data from sarcoma cell lines (n = 27) from Cancer Therapeutics Response Portal (CTRP) Version 2, potential predictive biomarkers of therapeutic response were identified. Results Genes associated with survival and/recurrence of these sarcomas with statistical significance were found on long arm of chromosome 8 and smaller aberrations were also identified at chromosomes 1q, 12q and x in OS, RMS, and ESFTs. A pool of 63 genes that harbored amplifications and/or deletions were frequently associated with recurrence across OS, RMS, and ESFTs. Correlation analysis of CNVs from CCLE with drug-response data of CTRP in 27 sarcoma cell lines, 33 CNVs out of 63 genes correlated with either sensitivity or resistance to 17 chemotherapies from which actionable CNV signatures such as IGF1R, MYC, MAPK1, ATF1, and MDM2 were identified. These CNV signatures could potentially be used to delineate patient populations that will respond versus those that will not respond to a particular chemotherapy. Conclusions The large-scale analyses of CNV-drug screening provides a platform to evaluate genetic alterations across aggressive pediatric sarcomas. Additionally, this study provides novel insights into the potential utilization of CNVs as not only prognostic but also as predictive biomarkers of therapeutic response. Information obtained in this study may help guide and prioritize patient-specific therapeutic options in pediatric bone and soft-tissue sarcomas. Electronic supplementary material The online version of this article (10.1186/s12920-018-0456-5) contains supplementary material, which is available to authorized users.Item Integrative Multi-OMICs Identifies Therapeutic Response Biomarkers and Confirms Fidelity of Clinically Annotated, Serially Passaged Patient-Derived Xenografts Established from Primary and Metastatic Pediatric and AYA Solid Tumors(MDPI, 2022-12-30) Pandya, Pankita H.; Jannu, Asha Jacob; Bijangi-Vishehsaraei, Khadijeh; Dobrota, Erika; Bailey, Barbara J.; Barghi, Farinaz; Shannon, Harlan E.; Riyahi, Niknam; Damayanti, Nur P.; Young, Courtney; Malko, Rada; Justice, Ryli; Albright, Eric; Sandusky, George E.; Wurtz, L. Daniel; Collier, Christopher D.; Marshall, Mark S.; Gallagher, Rosa I.; Wulfkuhle, Julia D.; Petricoin, Emanuel F.; Coy, Kathy; Trowbridge, Melissa; Sinn, Anthony L.; Renbarger, Jamie L.; Ferguson, Michael J.; Huang, Kun; Zhang, Jie; Saadatzadeh, M. Reza; Pollok, Karen E.; Pediatrics, School of MedicineEstablishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug−gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.Item Low serum albumin levels prior to pediatric allogeneic HCT are associated with increased need for critical care interventions and increased 6-month mortality(Wiley, 2017-09) Teagarden, Alicia M.; Skiles, Jodi L.; Beardsley, Andrew L.; Hobson, Michael J.; Moser, Elizabeth A. S.; Renbarger, Jamie L.; Rowan, Courtney M.; Pediatrics, School of MedicinePoor nutritional status in HCT patients is a negative prognostic factor. There are no pediatric studies evaluating albumin levels prior to HCT and need for critical care interventions. We hypothesized that pediatric patients with low albumin levels, routinely measured 30 days (±10 days) prior to allogeneic HCT, have a higher risk of critical care interventions in the post-transplant period. We performed a 5-year retrospective study of pediatric patients who underwent allogeneic HCT for any indication. Patients were categorized based on albumin level. Hypoalbuminemia was defined as <3.1 g/dL. A total of 73 patients were included, with a median age of 7.4 years (IQR 3.3, 13.2). Patients with hypoalbuminemia had higher needs for critical care interventions including non-invasive ventilation (44% vs 8%, P=.01), mechanical ventilation (67% vs 17%, P<.01), and vasoactive therapy (56% vs 16%, P=.01). Patients with hypoalbuminemia also had a higher 6-month mortality (56% vs 17%, P=.02). Our data demonstrate that children undergoing allogeneic HCT with hypoalbuminemia in the pretransplant period are more likely to require critical care interventions and have higher 6-month mortality. These findings identify an at-risk population in which nutritional improvements may be instituted prior to HCT in hopes of improving outcomes.