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Armstrong, Michael Brannon

Overview:

Neuroblastoma is the most common extra-cranial solid tumor of childhood. Despite advances in the treatment of childhood cancer, outcomes for children with advanced-stage neuroblastoma remain poor. My basic science research interests are focused on understanding the physiology of the neuroblastoma cell and what it does to circumvent the effects of chemotherapy. Additionally, I am interested in translational research in neuroblastoma. We have open trials for therapeutic MIBG and anti-GD2 antibody treatment for neuroblastoma. Clinically, I am involved in the treatment of childhood malignancies including neuroblasotma, soft tissue sarcomas, and leukemia. Additionally, I have an interest in the management of vascular malformations, such as hemangioma.

Positions:

Assistant Professor of Pediatrics

Pediatrics, Hematology-Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

Ph.D. — University of Minnesota, Twin Cities

M.D. 2001

M.D. — University of Minnesota, Twin Cities

Pediatric Residency, Pediatrics

University of Michigan at Ann Arbor

Pediatric Hematology/Oncology Fellowship, Pediatrics

University of Michigan at Ann Arbor

Grants:

DIV-NB-401

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
United Therapeutics Corporation
Role
Principal Investigator
Start Date
May 31, 2016
End Date
June 30, 2019

The impact of Mxi1 and Mxi0 on N-Myc function in neuroblastoma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Hyundai Hope on Wheels
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2017

Genetically Engineered Mouse Models of Neuroblasotma: the Impact of Mxi1 and Mxi0 Loss.

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Role of Exon 0 in the function of Mxi 0

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
June 08, 2015
End Date
August 14, 2015

Development of a Neuroblastoma Clinical Research Program

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Baldrick's Foundation
Role
Principal Investigator
Start Date
January 01, 2014
End Date
December 31, 2014
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Publications:

The role of Exon 0 in mediating Mxi0 activity in neuroblastoma

Authors
Kirchner, SJ; Bartram, JT; Ellis, DC; Wechsler, DS; Armstrong, MB
MLA Citation
Kirchner, SJ, Bartram, JT, Ellis, DC, Wechsler, DS, and Armstrong, MB. "The role of Exon 0 in mediating Mxi0 activity in neuroblastoma." March 1, 2016.
Source
wos-lite
Published In
Cancer Research
Volume
76
Publish Date
2016

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.

Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products.In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h).Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported.Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.

Authors
Marachelian, A; Desai, A; Balis, F; Katzenstein, H; Qayed, M; Armstrong, M; Neville, KA; Cohn, SL; Bush, M; Gunawan, R; Lim, AP; Smith, MA; Smith, LM
MLA Citation
Marachelian, A, Desai, A, Balis, F, Katzenstein, H, Qayed, M, Armstrong, M, Neville, KA, Cohn, SL, Bush, M, Gunawan, R, Lim, AP, Smith, MA, and Smith, LM. "Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy." Cancer chemotherapy and pharmacology 77.2 (February 2016): 405-412.
PMID
26791869
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
77
Issue
2
Publish Date
2016
Start Page
405
End Page
412
DOI
10.1007/s00280-015-2955-9

Mxi1 and mxi1-0 antagonize N-myc function and independently mediate apoptosis in neuroblastoma.

Neuroblastoma (NB) is the third most common malignancy of childhood, and outcomes for children with advanced disease remain poor; amplification of the MYCN gene portends a particularly poor prognosis. Mxi1 antagonizes N-Myc by competing for binding to Max and E-boxes. Unlike N-Myc, Mxi1 mediates transcriptional repression and suppresses cell proliferation. Mxi1 and Mxi1-0 (an alternatively transcribed Mxi1 isoform) share identical Max and DNA binding domains but differ in amino-terminal sequences. Because of the conservation of these critical binding domains, we hypothesized that Mxi1-0 antagonizes N-Myc activity similar to Mxi1. SHEP NB cells and SHEP cells stably transfected with MYCN (SHEP/MYCN) were transiently transfected with vectors containing full-length Mxi1, full-length Mxi1-0, or the common Mxi domain encoded by exons 2 to 6 (ex2-6). After incubation in low serum, parental SHEP/MYCN cell numbers were reduced compared with SHEP cells. Activated caspase-3 staining and DNA fragmentation ELISA confirmed that SHEP/MYCN cells undergo apoptosis in low serum, while SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 do not. However, SHEP/MYCN cells transfected with Mxi1 or Mxi1-0 and grown in normal serum showed proliferation rates similar to SHEP cells. Mxi ex2-6 did not affect cell number in low or normal serum, suggesting that amino terminal domains of Mxi1 and Mxi1-0 are critical for antagonism. In the absence of N-Myc, Mxi1 and Mxi1-0 induce apoptosis independently through the caspase-8-dependent extrinsic pathway, while N-Myc activates the caspase-9-dependent intrinsic pathway. Together, these data indicate that Mxi1 and Mxi1-0 antagonize N-Myc but also independently impact NB cell survival.

Authors
Erichsen, DA; Armstrong, MB; Wechsler, DS
MLA Citation
Erichsen, DA, Armstrong, MB, and Wechsler, DS. "Mxi1 and mxi1-0 antagonize N-myc function and independently mediate apoptosis in neuroblastoma." Translational oncology 8.1 (February 2015): 65-74.
PMID
25749179
Source
epmc
Published In
Translational oncology
Volume
8
Issue
1
Publish Date
2015
Start Page
65
End Page
74
DOI
10.1016/j.tranon.2015.01.002

N-Myc differentially regulates expression of MXI1 isoforms in neuroblastoma.

Amplification of the MYCN proto-oncogene is associated with a poor prognosis in patients with metastatic neuroblastoma (NB). MYCN encodes the N-Myc protein, a transcriptional regulator that dimerizes with the Max transcription factor, binds to E-box DNA sequences, and regulates genes involved in cell growth and apoptosis. Overexpression of N-Myc leads to transcriptional activation and an increase in NB cell proliferation. Mxi1, a member of the Myc family of transcriptional regulators, also binds to Max. However, Mxi1 is a transcriptional repressor and inhibits proliferation of NB cells, suggesting that Mxi1 functions as an N-Myc antagonist. Our laboratory previously identified Mxi1-0, an alternatively transcribed Mxi1 isoform. Mxi1-0 has properties distinct from those of Mxi1; in contrast to Mxi1, Mxi1-0 is unable to suppress c-Myc-dependent transcription. We now show that Mxi1-0 expression increases in response to MYCN overexpression in NB cells, with a positive correlation between MYCN and MXI1-0 RNA levels. We also show that N-Myc expression differentially regulates the MXI1 and MXI1-0 promoters: Increased MYCN expression suppresses MXI1 promoter activity while enhancing transcription through the MXI1-0 promoter. Finally, induction of Mxi1-0 leads to increased proliferation, whereas expression of Mxi1 inhibits cell growth, indicating differential roles for these two proteins. These data suggest that N-Myc differentially regulates the expression of MXI1 and MXI1-0 and can alter the balance between the two transcription factors. Furthermore, MXI1-0 appears to be a downstream target of MYCN-dependent signaling pathways and may contribute to N-Myc-dependent cell growth and proliferation.

Authors
Armstrong, MB; Mody, RJ; Ellis, DC; Hill, AB; Erichsen, DA; Wechsler, DS
MLA Citation
Armstrong, MB, Mody, RJ, Ellis, DC, Hill, AB, Erichsen, DA, and Wechsler, DS. "N-Myc differentially regulates expression of MXI1 isoforms in neuroblastoma." Neoplasia 15.12 (December 2013): 1363-1370.
PMID
24403858
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
15
Issue
12
Publish Date
2013
Start Page
1363
End Page
1370

Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-β receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, TβRIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. TβRIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. TβRIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. TβRIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for TβRIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.

Authors
Knelson, EH; Gaviglio, AL; Tewari, AK; Armstrong, MB; Mythreye, K; Blobe, GC
MLA Citation
Knelson, EH, Gaviglio, AL, Tewari, AK, Armstrong, MB, Mythreye, K, and Blobe, GC. "Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma." J Clin Invest 123.11 (November 2013): 4786-4798.
PMID
24216509
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
11
Publish Date
2013
Start Page
4786
End Page
4798
DOI
10.1172/JCI69657

Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Authors
Knelson, EH; Gaviglio, AL; Tewari, AK; Armstrong, MB; Nixon, AB; Starr, MD; Mythreye, K; Blobe, GC
MLA Citation
Knelson, EH, Gaviglio, AL, Tewari, AK, Armstrong, MB, Nixon, AB, Starr, MD, Mythreye, K, and Blobe, GC. "Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
5041
End Page
5041
DOI
10.1158/1538-7445.AM2013-5041

Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus.

Neuroblastoma is the most common solid tumor of infancy, and mutations in several genes have been implicated as playing a role in tumor development. Here, we describe a pediatric patient with a constitutional microduplication of 2p24.3 who developed Stage 4 neuroblastoma at age 11 months. He represents the sixth patient described in the literature with partial trisomy 2p and neuroblastoma. All previous cases had duplication events spanning two genes implicated in neuroblastoma, MYCN and ALK. Our patient is unique because his duplicated region includes the MYCN gene only; the ALK gene is unaffected. These data, combined with the relatively high incidence of neuroblastoma reported in partial trisomy 2p patients, support the notion that MYCN duplication should be added to the growing list of genetic factors associated with an increased risk of neuroblastoma. The mechanism of increased risk is unclear, but the fact that our patient had dramatic amplification of MYCN in his tumor suggests that a germline duplication might predispose to further amplification. Additionally, our patient has several morphologic features common to patients with partial trisomy 2p including high forehead, hypertelorism, postaxial polydactyly, and developmental delay despite having a microduplication spanning approximately 1 Mb and including just three intact genes. This case may therefore help further delineate the genotype-phenotype correlations associated with partial trisomy 2p.

Authors
Van Mater, D; Knelson, EH; Kaiser-Rogers, KA; Armstrong, MB
MLA Citation
Van Mater, D, Knelson, EH, Kaiser-Rogers, KA, and Armstrong, MB. "Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus." Am J Med Genet A 161A.3 (March 2013): 605-610.
PMID
23401364
Source
pubmed
Published In
American Journal of Medical Genetics Part A
Volume
161A
Issue
3
Publish Date
2013
Start Page
605
End Page
610
DOI
10.1002/ajmg.a.35766

Cardiac arrest and possible seizure activity after vincristine injection.

PURPOSE: A case of cardiac arrest and possible seizure activity after vincristine injection in a child is reported. SUMMARY: A two-year-old African-American girl with stage IV hepatoblastoma arrived at a clinic to receive her fourth dose of vincristine as part of standard induction therapy. The patient had tolerated her first three doses of vincristine sulfate 0.7 mg (1.5 mg/m(2)) i.v. without any adverse events. Laboratory tests, including a comprehensive metabolic panel, conducted before chemotherapy administration were unremarkable. Shortly after the administration of vincristine, the patient experienced tonic extension of all four extremities and upward sustained deviation of the eyes. The patient then became limp and exhibited perioral cyanosis. Further evaluation revealed a lack of central pulses and a heartbeat. Cardiopulmonary resuscitation was begun with chest compressions and positive-pressure ventilation via a bag-mask device. After approximately 45 seconds, her pulses returned, and perioral cyanosis resolved. She was admitted to the pediatric intensive care unit for further evaluation. Her serum electrolyte, glucose, and ammonia concentrations were within normal limits. No yeast or bacteria were isolated from the patient's blood. No contributing cardiac or neurologic factors were identified. The patient recovered without sequelae and was discharged after 72 hours. Subsequent doses of vincristine were administered with no adverse events, and the patient successfully completed her treatment regimen. CONCLUSION: A two-year-old girl with hepatoblastoma had seizurelike activity and cardiac arrest shortly after receiving i.v. vincristine. She received multiple doses of the drug before and after this event without a similar reaction. No contributing factors for the one-time event were identified.

Authors
Lennon, AS; Norales, G; Armstrong, MB
MLA Citation
Lennon, AS, Norales, G, and Armstrong, MB. "Cardiac arrest and possible seizure activity after vincristine injection." Am J Health Syst Pharm 69.16 (August 15, 2012): 1394-1397.
PMID
22855105
Source
pubmed
Published In
American Journal of Health-System Pharmacy
Volume
69
Issue
16
Publish Date
2012
Start Page
1394
End Page
1397
DOI
10.2146/ajhp110737

The PICALM protein plays a key role in iron homeostasis and cell proliferation.

The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM's function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR) internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs) that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation), all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.

Authors
Scotland, PB; Heath, JL; Conway, AE; Porter, NB; Armstrong, MB; Walker, JA; Klebig, ML; Lavau, CP; Wechsler, DS
MLA Citation
Scotland, PB, Heath, JL, Conway, AE, Porter, NB, Armstrong, MB, Walker, JA, Klebig, ML, Lavau, CP, and Wechsler, DS. "The PICALM protein plays a key role in iron homeostasis and cell proliferation." PLoS One 7.8 (2012): e44252-.
PMID
22952941
Source
pubmed
Published In
PloS one
Volume
7
Issue
8
Publish Date
2012
Start Page
e44252
DOI
10.1371/journal.pone.0044252

Immune therapies for neuroblastoma.

Neuroblastoma, a solid tumor arising from developing cells of the sympathetic nervous system, is the most common extracranial tumor in children. The prognosis for high-risk neuroblastoma remains poor with conventional treatment, and new approaches are therefore being explored to treat this disease. One such alternative therapy that holds promise is immune therapy. We review here the recent advances in four types of immune therapy-cytokine, vaccine, antibody and cellular therapy-to treat neuroblastoma. We present preclinical research and clinical trials on several promising candidates such as IL-12, dendritic cell vaccines, anti-GD2 antibodies and allogeneic hematopoietic stem cell transplant. An optimal treatment plan for neuroblastoma will most likely involve multimodal approaches and combinations of immune therapies.

Authors
Navid, F; Armstrong, M; Barfield, RC
MLA Citation
Navid, F, Armstrong, M, and Barfield, RC. "Immune therapies for neuroblastoma." Cancer Biol Ther 8.10 (May 2009): 874-882. (Review)
PMID
19342881
Source
pubmed
Published In
Cancer Biology and Therapy
Volume
8
Issue
10
Publish Date
2009
Start Page
874
End Page
882

Bortezomib as a therapeutic candidate for neuroblastoma.

Outcomes remain poor in neuroblastoma despite intensive treatment. Agents with potential efficacy can be drawn from anti-neoplastic drugs introduced for other malignancies. Bortezomib, a proteasome inhibitor, modulates cell-signaling molecules leading to apoptosis. Bortezomib, alone and in combination with other agents, was tested across an in vitro panel of neuroblastic, stromal, and chemo-resistant neuroblastoma cell types to determine its effect on cell viability and to assess for interactions between bortezomib and other chemotherapeutic agents that either limit or increase overall response. Each subtype of neuroblastoma was sensitive to bortezomib and killing occurred with EC50 values of approximately 50 nM. When bortezomib was combined with other agents (doxorubicin, etoposide, SN-38, carboplatin, or cisplatin), no antagonism was observed. The bortezomib-doxorubicin combination was especially effective, demonstrating synergy on isobolographic analysis and resulting in a decrease in EC50 from 50 ng/mL with doxorubicin alone to 5 ng/mL with 25 nM bortezomib. Interestingly, the different cell types exhibited varying response patterns to treatment with bortezomib alone and in combination with other drugs suggesting different mechanisms may be engaged. A decision analysis, incorporating these results showing efficacy in all cell types, the synergy obtained in combination, and the available toxicity data, supports a phase II clinical trial of bortezomib in neuroblastoma.

Authors
Armstrong, MB; Schumacher, KR; Mody, R; Yanik, GA; Opipari, AW; Castle, VP
MLA Citation
Armstrong, MB, Schumacher, KR, Mody, R, Yanik, GA, Opipari, AW, and Castle, VP. "Bortezomib as a therapeutic candidate for neuroblastoma." J Exp Ther Oncol 7.2 (2008): 135-145.
PMID
18771087
Source
pubmed
Published In
Journal of experimental therapeutics & oncology
Volume
7
Issue
2
Publish Date
2008
Start Page
135
End Page
145

Signaling from p53 to NF-kappa B determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-kappaB (I-KB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.

Authors
Armstrong, MB; Bian, X; Liu, Y; Subramanian, C; Ratanaproeksa, AB; Shao, F; Yu, VC; Kwok, RPS; Opipari, AW; Castle, VP
MLA Citation
Armstrong, MB, Bian, X, Liu, Y, Subramanian, C, Ratanaproeksa, AB, Shao, F, Yu, VC, Kwok, RPS, Opipari, AW, and Castle, VP. "Signaling from p53 to NF-kappa B determines the chemotherapy responsiveness of neuroblastoma." Neoplasia 8.11 (November 2006): 964-974.
PMID
17215959
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
8
Issue
11
Publish Date
2006
Start Page
964
End Page
974

Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-kappaB (I-kappaB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.

Authors
Armstrong, MB; Bian, X; Liu, Y; Subramanian, C; Ratanaproeksa, AB; Shao, F; Yu, VC; Kwok, RPS; Opipari, AW; Castle, VP
MLA Citation
Armstrong, MB, Bian, X, Liu, Y, Subramanian, C, Ratanaproeksa, AB, Shao, F, Yu, VC, Kwok, RPS, Opipari, AW, and Castle, VP. "Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma." Neoplasia 8.11 (November 2006): 967-977.
PMID
17132229
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
8
Issue
11
Publish Date
2006
Start Page
967
End Page
977
DOI
10.1593/neo.06574

Delayed, recurrent opsoclonus-myoclonus syndrome responding to plasmapheresis.

Opsoclonus-myoclonus syndrome is a distinct neurologic disorder characterized by opsoclonic eye movements, multifocal myoclonus, and ataxia, traditionally described as "dancing eyes, dancing feet." A presenting sign in 2% of children with neuroblastoma, it usually heralds a favorable prognosis for the tumor. Although opsoclonus-myoclonus syndrome usually presents at initial diagnosis or relapse, there are reports of delayed presentation, usually a few months after diagnosis. This report describes a patient with ganglioneuroblastoma who developed recurrent symptoms of opsoclonus-myoclonus syndrome 9 years after completing treatment, without evidence of recurrent tumor. Believed to be autoimmune in origin, opsoclonus-myoclonus syndrome frequently responds to immunomodulatory therapies, such as steroids or intravenous immunoglobulin. This patient did not respond adequately to either agent, so plasmapheresis, a less commonly used modality in opsoclonus-myoclonus syndrome, was attempted. His symptoms resolved after he received therapy with a combination of plasmapheresis and steroids over a 1-year period. After being slowly weaned off all therapy, he has been symptom-free now for over 3 years. Armstrong MB, Robertson PL, Castle VP. Delayed, recurrent opsoclonus-myoclonus syndrome responding to plasmapheresis.

Authors
Armstrong, MB; Robertson, PL; Castle, VP
MLA Citation
Armstrong, MB, Robertson, PL, and Castle, VP. "Delayed, recurrent opsoclonus-myoclonus syndrome responding to plasmapheresis." Pediatr Neurol 33.5 (November 2005): 365-367.
PMID
16243225
Source
pubmed
Published In
Pediatric Neurology
Volume
33
Issue
5
Publish Date
2005
Start Page
365
End Page
367
DOI
10.1016/j.pediatrneurol.2005.05.018

Testicular chloroma in a nonleukemic infant.

Extramedullary myeloid cell tumors (EMCT) are localized collections of immature myeloid cells that occur outside of the bone marrow. Usually observed concurrently with bone marrow disease, EMCT also may occur in the absence of overt marrow leukemia. In this report, we describe an infant with a testicular mass that was identified as an EMCT after orchiectomy. Unlike the only previously reported case of infantile testicular chloroma, this patient did not exhibit bone marrow disease at diagnosis. Because systemic chemotherapy is considered to be superior to local control (surgery, radiation therapy), the patient was treated with intensively timed induction chemotherapy followed by 3 cycles of maintenance treatment (according to CCG protocol #2891) but no radiation therapy. The patient remains disease-free 18 months after diagnosis.

Authors
Armstrong, MB; Nafiu, OO; Valdez, R; Park, JM; Williams, JA; Wechsler, DS
MLA Citation
Armstrong, MB, Nafiu, OO, Valdez, R, Park, JM, Williams, JA, and Wechsler, DS. "Testicular chloroma in a nonleukemic infant." J Pediatr Hematol Oncol 27.7 (July 2005): 393-396.
PMID
16012331
Source
pubmed
Published In
Journal of Pediatric Hematology/Oncology
Volume
27
Issue
7
Publish Date
2005
Start Page
393
End Page
396

Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARalpha-mediated pathway.

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP-2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control other energy-related metabolic processes. Treatment with 250 microM palmitic acid was without effect on UCP-2 expression, whereas 250 microM oleic acid exhibited a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentration dependent. This effect was seen within 12 h and was maximal by 36 h. Aspirin blocked the induction of UCP-2 by EPA, indicating involvement of the prostaglandin pathway. Hepatocytes treated with arachidonic acid, the immediate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostaglandins in regulating hepatic UCP-2. The peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist Wy-14643 stimulated UCP-2 mRNA levels as effectively as EPA. These data indicate that UCP-2 is upregulated by polyunsaturated fatty acids, potentially through a prostaglandin/PPARalpha-mediated pathway.

Authors
Armstrong, MB; Towle, HC
MLA Citation
Armstrong, MB, and Towle, HC. "Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARalpha-mediated pathway." Am J Physiol Endocrinol Metab 281.6 (December 2001): E1197-E1204.
PMID
11701434
Source
pubmed
Published In
American journal of physiology. Endocrinology and metabolism
Volume
281
Issue
6
Publish Date
2001
Start Page
E1197
End Page
E1204

Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP-2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control other energy-related metabolic processes. Treatment with 250 μM palmitic acid was without effect on UCP-2 expression, whereas 250 μM oleic acid exhibited a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentration dependent. This effect was seen within 12 h and was maximal by 36 h. Aspirin blocked the induction of UCP-2 by EPA, indicating involvement of the prostaglandin pathway. Hepatocytes treated with arachidonic acid, the immediate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostaglandins in regulating hepatic UCP-2. The peroxisome proliferator-activated receptor-αα (PPARα) agonist Wy-14643 stimulated UCP-2 mRNA levels as effectively as EPA. These data indicate that UCP-2 is upregulated by polyunsaturated fatty acids, potentially through a prostaglandin/PPARα-mediated pathway. Copyright © 2001 the American Physiological Society.

Authors
Armstrong, MB; Towle, HC
MLA Citation
Armstrong, MB, and Towle, HC. "Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway." American Journal of Physiology 281.6 PART 1 (2001): E1249-E1254.
Source
scival
Published In
The American journal of physiology
Volume
281
Issue
6 PART 1
Publish Date
2001
Start Page
E1249
End Page
E1254

Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP-2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control other energy-related metabolic processes. Treatment with 250 μM palmitic acid was without effect on UCP-2 expression, whereas 250 μM oleic acid exhibited a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentration dependent. This effect was seen within 12 h and was maximal by 36 h. Aspirin blocked the induction of UCP-2 by EPA, indicating involvement of the prostaglandin pathway. Hepatocytes treated with arachidonic acid, the immediate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostaglandins in regulating hepatic UCP-2. The peroxisome proliferator-activated receptors-α (PPARα) agonist Wy-14643 stimulated UCP-2 mRNA levels as effectively as EPA. These data indicate that UCP-2 is upregulated by polyunsaturated fatty acids, potentially through a prostaglandin/PPARα-mediated pathway.

Authors
Armstrong, MB; Towle, HC
MLA Citation
Armstrong, MB, and Towle, HC. "Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway." American Journal of Physiology - Endocrinology and Metabolism 281.6 44-6 (2001): E1197-E1204.
Source
scival
Published In
American journal of physiology. Endocrinology and metabolism
Volume
281
Issue
6 44-6
Publish Date
2001
Start Page
E1197
End Page
E1204

Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet.

The enzyme cyclooxygenase (COX)-1 is constitutive whereas COX-2 is regulated in virtually all tissues. To assess whether this dogma holds true in the pancreatic islet, we examined basal and interleukin (IL)-1-regulated expression of COX-2 in HIT-T15 cells, Syrian hamster and human islets, and other Syrian hamster tissues. We found that COX-2, and not COX-1, gene expression is dominant in pancreatic islet tissue under both basal and IL-1-stimulated conditions. Control tissues (liver, spleen, and kidney) showed the expected predominance of COX-1 gene expression. Basal and IL-1-stimulated prostaglandin E2 synthesis were blocked by a specific COX-2 inhibitor. IL-1 stimulation had a biphasic effect on COX-2 mRNA levels with an initial mild increase at 2-4 hr followed by a more dramatic decrease below basal level by 24 hr. The IL-1-induced increase in COX-2 mRNA levels was accompanied by a parallel increase in NF-kappaB binding to COX-2 promoter elements. The subsequent decrease in COX-2 mRNA levels was accompanied by a parallel decrease in NF-IL-6 binding activity and COX-2 promoter activity. Specific mutation of the NF-IL-6 binding motif within the COX-2 promoter reduced basal promoter activity by 50% whereas mutation of the NF-kappaB motif had no effect. These studies provide documentation of NF-IL-6 in the pancreatic islet and that COX-2, rather than COX-1, is dominantly expressed. They suggest coordinate regulation by IL-1 of COX-2 mRNA, NF-kappaB, and NF-IL-6 and raise the issue of whether intrinsically high levels of COX-2 gene expression predisposes the normal islet for microenvironmentally induced overproduction of islet prostaglandin E2.

Authors
Sorli, CH; Zhang, HJ; Armstrong, MB; Rajotte, RV; Maclouf, J; Robertson, RP
MLA Citation
Sorli, CH, Zhang, HJ, Armstrong, MB, Rajotte, RV, Maclouf, J, and Robertson, RP. "Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet." Proc Natl Acad Sci U S A 95.4 (February 17, 1998): 1788-1793.
PMID
9465095
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
95
Issue
4
Publish Date
1998
Start Page
1788
End Page
1793

Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells.

FK506 (tacrolimus) is an immunosuppressive drug which interrupts Ca2+-calmodulin-calcineurin signaling pathways in T lymphocytes, thereby blocking antigen activation of T cell early activation genes. Regulation of insulin gene expression in the beta cell may also involve Ca2+-signaling pathways and FK506 has been associated with insulin-requiring diabetes mellitus during clinical use. The purpose of this study was to characterize the effects of FK506 on human insulin gene transcription, insulin mRNA levels, and insulin secretion using as a model the HIT-T15 beta cell line. FK506 had no acute effect on insulin secretion in the HIT cell, but caused a reversible time- and dose-dependent (10(-9)-10(-6) M) decrease in HIT cell insulin secretion. Decreased insulin secretion in the presence of FK506 was also accompanied by a dose-dependent decrease in HIT cell insulin content, insulin mRNA levels, and expression of a human insulin promoter-chloramphenicol acetyl transferase (CAT) reporter gene. FK506 decreased HIT cell expression of the human insulin promoter-CAT reporter gene by 40% in the presence of both low (0.4 mM) at high (20 mM) glucose concentrations. Western blot analysis of HIT cell proteins gave evidence for the presence of calcineurin in the HIT cell. These findings suggest that FK506 may have direct effects to reversibly inhibit insulin gene transcription, leading to a decline in insulin mRNA levels, insulin synthesis, and ultimately insulin secretion.

Authors
Redmon, JB; Olson, LK; Armstrong, MB; Greene, MJ; Robertson, RP
MLA Citation
Redmon, JB, Olson, LK, Armstrong, MB, Greene, MJ, and Robertson, RP. "Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells." J Clin Invest 98.12 (December 15, 1996): 2786-2793.
PMID
8981925
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
98
Issue
12
Publish Date
1996
Start Page
2786
End Page
2793
DOI
10.1172/JCI119105

Morphological and functional characterization of beta TC-6 cells--an insulin-secreting cell line derived from transgenic mice.

Morphological analysis of hormone content and functional assessment of hormone secretion were conducted in beta TC-6 cells, an insulin-secreting cell line derived from transgenic mice expressing the large T-antigen of simian virus 40 (SV40) in pancreatic beta-cells. We observed by immunohistochemistry and confocal microscopy that beta TC-6 cells contain abundant insulin and small amounts of glucagon and somatostatin (SRIF). Glucagon usually co-localized with insulin, whereas cells containing SRIF did not contain insulin or glucagon. Static incubation and perifusion experiments demonstrated that beta TC-6 cells at passage 30-45 secrete insulin in response to glucose. In static incubations, maximal stimulation was achieved for glucose concentrations > 2.8 mmol/l glucose, and the half-maximal effect was observed at 0.5 mmol/l. Maximal stimulation was four times greater than HIT-T15 cells at passage 72-81, although HIT cells had a greater response over their basal levels. The magnitude of the insulin response to glucose in perifusion was 1,734 +/- 384 pmol.l-1. min and was 4.6-fold greater in the presence of 3-isobutyl-1-methylxanthine. Low amounts of glucagon were released in response to amino acids. Epinephrine (EPI), and to a lesser extent SRIF, inhibited phasic glucose-induced insulin secretion. A major portion of these inhibitory effects was mediated by pertussis toxin-sensitive substrates. Immunoblots detected the presence of the G-proteins Gi alpha 2, Gi alpha 3, and Go alpha 2. These results indicate that beta TC-6 cells are a glucose-responsive cell line in which insulin exocytosis is physiologically regulated by EPI and SRIF through Gi/Go-mediated mechanisms.

Authors
Poitout, V; Stout, LE; Armstrong, MB; Walseth, TF; Sorenson, RL; Robertson, RP
MLA Citation
Poitout, V, Stout, LE, Armstrong, MB, Walseth, TF, Sorenson, RL, and Robertson, RP. "Morphological and functional characterization of beta TC-6 cells--an insulin-secreting cell line derived from transgenic mice." Diabetes 44.3 (March 1995): 306-313.
PMID
7533732
Source
pubmed
Published In
Diabetes
Volume
44
Issue
3
Publish Date
1995
Start Page
306
End Page
313

Somatostatin selectively couples to G(o) alpha in HIT-T15 cells.

Previously, we have demonstrated that somatostatin mediates all of its inhibitory effects on glucose-induced insulin secretion from the HIT-T15 cell through pertussis toxin-sensitive G-proteins and that the membrane fraction of this clonal line of pancreatic beta-cells contains six such proteins: G(i) alpha 1, G(i) alpha 2, G(i) alpha 3, and three forms of G(o) alpha. To determine the specificity of somatostatin receptor-G-protein coupling in HIT-T15 cells, we examined the ability of antisera specific for the COOH-terminus of G alpha subtypes to inhibit somatostatin-induced augmentation of membrane GTPase activity. GTPase activity increased in membranes as a function of GTP. At all concentrations of GTP studied, 1 mumol/l somatostatin stimulated GTPase activity. Pertussis-toxin pretreatment prevented the effects of somatostatin. Antisera selective for G(o) alpha subtypes reduced the effects of somatostatin on GTPase activity (GTPase activity in absence of antisera, 125 +/- 3% of control; in the presence of antisera 976, 110 +/- 2% of control; n = 13, P < 0.001), whereas antisera directed against G(i) alpha 1, G(i) alpha 2, G(i) alpha 3, and Gs alpha were without effect. Somatostatin also significantly prevented cyclic AMP accumulation during perifusion with 11.1 mmol/l glucose through a pertussis toxin-sensitive mechanism. These data indicate that the somatostatin receptor couples to G(o) alpha in the HIT-T15 cell and suggest that G(o) alpha may link somatostatin to cyclic AMP metabolism in pancreatic beta-cells.

Authors
Seaquist, ER; Armstrong, MB; Gettys, TW; Walseth, TF
MLA Citation
Seaquist, ER, Armstrong, MB, Gettys, TW, and Walseth, TF. "Somatostatin selectively couples to G(o) alpha in HIT-T15 cells." Diabetes 44.1 (January 1995): 85-89.
PMID
7813819
Source
pubmed
Published In
Diabetes
Volume
44
Issue
1
Publish Date
1995
Start Page
85
End Page
89
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