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Results: 1 to 10 of 73

Publication Record


AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.
Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, Macintyre AN, Goraksha-Hicks P, de Cubas AA, Liu T, Warmoes MO, Abel ED, Yeoh AE, Gershon TR, Rathmell WK, Richards KL, Locasale JW, Rathmell JC
(2016) Cell Metab 23: 649-62
MeSH Terms: AMP-Activated Protein Kinases, Animals, Cell Line, Tumor, Cell Survival, Glycolysis, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Inbred C57BL, Mitochondria, Multiprotein Complexes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Notch, Signal Transduction, Stress, Physiological, T-Lymphocytes, TOR Serine-Threonine Kinases
Show Abstract · Added August 8, 2016
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia.
Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, Basford M, Bastarache L, Roden DM, Denny JC, Larsen E, Winick N, Carroll WL, Cheng C, Pei D, Fernandez CA, Liu C, Smith C, Loh ML, Raetz EA, Hunger SP, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Mattano LA, Relling MV
(2015) Blood 126: 1770-6
MeSH Terms: Biomarkers, Child, Cohort Studies, Dexamethasone, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucocorticoids, Humans, Male, Meta-Analysis as Topic, Neoplasm Staging, Osteonecrosis, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Receptors, N-Methyl-D-Aspartate, Risk Factors
Show Abstract · Added April 11, 2017
Glucocorticoids are important therapy for acute lymphoblastic leukemia (ALL) and their major adverse effect is osteonecrosis. Our goal was to identify genetic and nongenetic risk factors for osteonecrosis. We performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort comprising 2285 children with ALL, treated on the Children's Oncology Group AALL0232 protocol (NCT00075725), adjusting for covariates. The minor allele at SNP rs10989692 (near the glutamate receptor GRIN3A locus) was associated with osteonecrosis (hazard ratio = 2.03; P = 3.59 × 10(-7)). The association was supported by 2 replication cohorts, including 361 children with ALL on St. Jude's Total XV protocol (NCT00137111) and 309 non-ALL patients from Vanderbilt University's BioVU repository treated with glucocorticoids (odds ratio [OR] = 1.87 and 2.26; P = .063 and .0074, respectively). In a meta-analysis, rs10989692 was also highest ranked (P = 2.68 × 10(-8)), and the glutamate pathway was the top ranked pathway (P = 9.8 × 10(-4)). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR = 1.64; P = 2.5 × 10(-3)), and arterial embolism and thrombosis (OR = 1.88; P = 4.2 × 10(-3)). In conclusion, osteonecrosis was associated with inherited variations near glutamate receptor genes. Further understanding this association may allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.
© 2015 by The American Society of Hematology.
0 Communities
2 Members
0 Resources
19 MeSH Terms
Patterns and severity of vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia.
Lavoie Smith EM, Li L, Chiang C, Thomas K, Hutchinson RJ, Wells EM, Ho RH, Skiles J, Chakraborty A, Bridges CM, Renbarger J
(2015) J Peripher Nerv Syst 20: 37-46
MeSH Terms: Adolescent, Antineoplastic Agents, Phytogenic, Child, Child, Preschool, Female, Humans, Infant, Male, Pain Measurement, Peripheral Nervous System Diseases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Severity of Illness Index, Vincristine
Show Abstract · Added November 10, 2016
Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.
© 2015 Peripheral Nerve Society.
0 Communities
1 Members
0 Resources
13 MeSH Terms
PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin.
Ondrejka SL, Jegalian AG, Kim AS, Chabot-Richards DS, Giltnane J, Czuchlewski DR, Shetty S, Sekeres MA, Yenamandra A, Head D, Jagasia M, Hsi ED
(2014) Haematologica 99: e148-51
MeSH Terms: Adult, Bone Marrow, Gene Expression, Humans, Karyotype, Leukemia, Myeloid, Male, Middle Aged, Neoplastic Stem Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Platelet-Derived Growth Factor beta, Translocation, Genetic
Added January 20, 2015
0 Communities
1 Members
0 Resources
12 MeSH Terms
Safety of high dose trivalent inactivated influenza vaccine in pediatric patients with acute lymphoblastic leukemia.
McManus M, Frangoul H, McCullers JA, Wang L, O'Shea A, Halasa N
(2014) Pediatr Blood Cancer 61: 815-20
MeSH Terms: Adolescent, Antibodies, Viral, Child, Child, Preschool, Double-Blind Method, Drug-Related Side Effects and Adverse Reactions, Female, Follow-Up Studies, Hemagglutination Inhibition Tests, Humans, Influenza A virus, Influenza Vaccines, Influenza, Human, Injections, Intramuscular, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Risk Factors, Vaccination, Vaccines, Inactivated
Show Abstract · Added March 27, 2014
BACKGROUND - Although children with acute lymphoblastic leukemia (ALL) mount immune responses after vaccination with the trivalent influenza vaccine (TIV), these responses are lower compared to controls. Recently, a high dose (HD) TIV was found to increase the level of antibody response in elderly patients compared to the standard dose (SD) TIV. We hypothesized that the HD TIV would be well-tolerated and more immunogenic compared to the SD TIV in pediatric subjects with ALL.
PROCEDURE - This was a randomized, double-blind, phase I safety trial comparing the HD to the SD TIV in children with ALL. Our secondary objective was immunogenicity. Subjects were randomized 2:1 to receive either the HD (60 µg) or the SD (15 µg) TIV. Local and systemic reactions were solicited, hemagglutinin inhibition titers to influenza virus antigens were measured, and monitoring labs were collected prior to and/or after each vaccination.
RESULTS - Fifty subjects were enrolled (34 HD, 16 SD). Mean age was 8.5 years; 63% were male, and 80% were in maintenance therapy. There were no significant differences reported in local or systemic symptoms. No severe adverse events were attributed to vaccination. No significant differences between the HD and SD TIV groups were noted for immune responses.
CONCLUSIONS - No differences were noted between the HD and SD TIV groups for solicited systemic and local reactions. Since this study was not powered for immunogenicity, a phase II trial is needed to determine the immunogenicity of HD versus SD TIV in the pediatric ALL population.
© 2013 Wiley Periodicals, Inc.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Tobacco smoke exposure and the risk of childhood acute lymphoblastic and myeloid leukemias by cytogenetic subtype.
Metayer C, Zhang L, Wiemels JL, Bartley K, Schiffman J, Ma X, Aldrich MC, Chang JS, Selvin S, Fu CH, Ducore J, Smith MT, Buffler PA
(2013) Cancer Epidemiol Biomarkers Prev 22: 1600-11
MeSH Terms: Adolescent, California, Case-Control Studies, Child, Child, Preschool, Cytogenetics, Female, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Male, Multivariate Analysis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pregnancy, Prenatal Exposure Delayed Effects, Risk Factors, Tobacco Smoke Pollution
Show Abstract · Added February 26, 2014
BACKGROUND - Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect of tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of prenatal origin such as ALL with translocation t(12;21) or high-hyperdiploidy (51-67 chromosomes).
METHODS - We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996-2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in situ hybridization.
RESULTS - Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and child's passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL [95% confidence interval (CI), 1.01-2.23], compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR = 2.08; 95% CI, 1.04-4.16), but not high hyperdiploid B-cell ALL. Similarly, child's passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR = 2.76; 95% CI, 1.01-7.58), but not aneuploidy.
CONCLUSIONS - Our data suggest that exposure to tobacco smoking was associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates.
IMPACT - Parents should limit exposures to tobacco smoke before and after the child's birth.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia.
Lavoie Smith EM, Li L, Hutchinson RJ, Ho R, Burnette WB, Wells E, Bridges C, Renbarger J
(2013) Cancer Nurs 36: E49-60
MeSH Terms: Adolescent, Antineoplastic Agents, Phytogenic, Child, Child, Preschool, Clinical Trials as Topic, Feasibility Studies, Female, Humans, Infant, Male, Nursing Assessment, Pain Measurement, Peripheral Nervous System Diseases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Reproducibility of Results, Severity of Illness Index, Tissue Distribution, United States, Vincristine
Show Abstract · Added March 5, 2014
BACKGROUND - Vincristine-induced peripheral neuropathy (VIPN) is difficult to quantify in children.
OBJECTIVE - The study objective was to examine the reliability, validity, and clinical feasibility of several VIPN measures for use in children with acute lymphoblastic leukemia.
INTERVENTIONS/METHODS - Children (n = 65) aged 1 to 18 years receiving vincristine at 4 academic centers participated in the study. Baseline and pre-vincristine administration VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), the National Cancer Institute Common Terminology Criteria for Adverse Events, the Balis grading scale, and the FACES Pain Scale. The TNS-PV scores (n = 806) were obtained over 15 weeks. Blood was obtained at several time points to quantify pharmacokinetic parameters.
RESULTS - Cronbach's α for a reduced TNS-PV scale was .84. The TNS-PV scores correlated with cumulative vincristine dosage (r = 0.53, P = 0.01), pharmacokinetic parameters (r = 0.41, P = 0.05), and grading scale scores (r range = 0.46-0.52, P = .01). FACES scores correlated with the TNS-PV neuropathic pain item (r = 0.48; P = .01) and were attainable in all ages. A 2-item V-Rex score (vibration and reflex items) was the most responsive to change (effect size = 0.65, P < 0.001). The TNS-PV scores were attainable in 95% of children 6 years or older.
CONCLUSIONS - The TNS-PV is reliable and valid for measuring VIPN. It is sensitive to change over time (15 weeks) and feasible for use in children 6 years or older.
IMPLICATIONS FOR PRACTICE - The TNS-PV may be a useful tool for assessing vincristine toxicity in children with acute lymphoblastic leukemia.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Risk of subsequent malignancies in survivors of childhood leukemia.
Perkins SM, Dewees T, Shinohara ET, Reddy MM, Frangoul H
(2013) J Cancer Surviv 7: 544-50
MeSH Terms: Adolescent, Adult, Age of Onset, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Neoplasms, Second Primary, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Risk Factors, Survivors, Young Adult
Show Abstract · Added March 7, 2014
PURPOSE - The diagnosis of childhood leukemia now carries a much improved overall survival. With this knowledge comes concern for late effects of therapy, especially the risk of secondary malignancy.
METHODS - Patients diagnosed with AML or ALL between the ages of 0 and 18 years who survived at least 5 years after diagnosis were included in analysis. Cumulative incidence of subsequent malignancy at 30 years was calculated. To compare incidence of subsequent malignancies with rates of the US population, standardized incidence ratios (SIRs) were calculated.
RESULTS - Four thousand eight hundred six patients were included in the analysis. Median follow-up was 14.5 years (range 5.0-35.9 years). A total of 82 patients developed a second malignancy. The most common second tumor was brain (24 %) followed by thyroid (22 %). Cumulative incidences of secondary malignancy at 30 years for ALL patients and AML patients were 3.9 and 4.3 %, respectively (p = 0.10). Patients were at an increased risk of malignancy compared to the US population (SIR = 3.9, 95 % CI = 3.2-4.8). The SIR for all malignancies for patients diagnosed between 1973 and 1979, 1980 and 1989, and 1990 and 1999 were 2.1 (95 % CI = 1.3-3.4), 4.3 (95 % CI = 3.1-5.9), and 4.4 (95 % CI = 2.7-6.6), respectively.
CONCLUSIONS - Although incidence of secondary malignancy at 30 years in survivors of childhood leukemia is low, the rate exceeds the expected rate of malignancy for a cohort of this age by nearly 4:1. The development of a subsequent malignancy has significant impact on overall-survival and continued research is needed to assess the long-term risk of subsequent malignancy with modern therapy.
IMPLICATIONS FOR CANCER SURVIVORS - Although survivors of childhood leukemia experience an increased rate of malignancy compared to their peers, the development of a subsequent malignancy is still a rare event. However, continued long-term follow-up is warranted.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy.
Esbenshade AJ, Simmons JH, Koyama T, Lindell RB, Friedman DL
(2013) Pediatr Blood Cancer 60: 1287-91
MeSH Terms: Adolescent, Adult, Blood Glucose, Body Mass Index, Child, Child, Preschool, Fasting, Female, Follow-Up Studies, Humans, Insulin, Insulin Resistance, Leptin, Male, Obesity, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prospective Studies, Triglycerides
Show Abstract · Added March 7, 2014
BACKGROUND - Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy.
PROCEDURE - In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin.
RESULTS - Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively).
CONCLUSIONS - Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors.
Copyright © 2013 Wiley Periodicals, Inc.
0 Communities
3 Members
0 Resources
18 MeSH Terms
Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia.
Chow EJ, Pihoker C, Friedman DL, Lee SJ, McCune JS, Wharton C, Roth CL, Baker KS
(2013) Pediatr Blood Cancer 60: 621-6
MeSH Terms: Adolescent, Antineoplastic Agents, Body Mass Index, Child, Child, Preschool, Female, Glucocorticoids, Humans, Hyperinsulinism, Insulin Resistance, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Young Adult
Show Abstract · Added March 7, 2014
BACKGROUND - Children treated for acute lymphoblastic leukemia (ALL) are more likely to become overweight. Prolonged exposure to high-dose glucocorticoids may cause insulin resistance and facilitate development of this phenotype.
PROCEDURE - Body mass indices (BMI) and insulin resistance (homeostatic model assessment [HOMA]-IR) were prospectively measured among on- (n = 31) and off-therapy participants (n = 29). On-therapy participants were assessed prior to and while on glucocorticoids (5 days of prednisone 40 mg m(-2) or dexamethasone 6 mg m(-2)) given as part of routine maintenance chemotherapy, with a subset (n = 10) receiving an intravenous glucose tolerance test (IVGTT) while on glucocorticoids.
RESULTS - Baseline HOMA-IR values among on- and off-therapy participants were similar, but among on-therapy participants, HOMA-IR increased significantly with glucocorticoid exposure (median 3.39 vs. 1.26; P < 0.01) with 45.2% of participants having values >4.39 (upper 2.5th percentile among normal weight adolescents). Although baseline HOMA-IR was significantly correlated with current BMI (r = 0.48, P < 0.01), change in HOMA-IR following steroid exposure was not correlated with any demographic or treatment characteristic including current BMI. Among those with IVGTT data, HOMA estimates in general correlated with values derived from a minimal model analysis (r ~ 0.7).
CONCLUSIONS - High-dose glucocorticoids given as part of routine chemotherapy were associated with a significantly increased insulin resistant state. Given the amount and duration of glucocorticoids children with ALL experience, these physiologic changes could be an important contributor to the development of therapy-related obesity.
Copyright © 2012 Wiley Periodicals, Inc.
0 Communities
1 Members
0 Resources
13 MeSH Terms