Giselle L. Saulnier Sholler

Helen DeVos Children's Hospital, Grand Rapids, Michigan, United States

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Publications (21)66.37 Total impact

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    ABSTRACT: The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Cancer Medicine 02/2015; DOI:10.1002/cam4.436
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    ABSTRACT: LIN28 has emerged as an oncogenic driver in a number of cancers, including neuroblastoma (NB). Overexpression of LIN28 correlates with poor outcome in NB, therefore drugs that impact the LIN28/Let-7 pathway could be beneficial in treating NB patients. The LIN28/Let-7 pathway affects many cellular processes including the regulation of cancer stem cells and glycolytic metabolism. Polyamines, regulated by ornithine decarboxylase (ODC) modulate eIF-5A which is a direct regulator of the LIN28/Let-7 axis. We propose that therapy inhibiting ODC will restore balance to the LIN28/Let-7 axis, suppress glycolytic metabolism, and decrease MYCN protein expression in NB. Difluoromethylornithine (DFMO) is an inhibitor of ODC in clinical trials for children with NB. In vitro experiments using NB cell lines, BE(2)-C, SMS-KCNR, and CHLA90 show that DFMO treatment reduced LIN28B and MYCN protein levels and increased Let-7 miRNA and decreased neurosphere formation. Glycolytic metabolic activity decreased with DFMO treatment in vivo. Additionally, sensitivity to DFMO treatment correlated with LIN28B overexpression (BE(2)-C>SMS-KCNR>CHLA90). This is the first study to demonstrate that DFMO treatment restores balance to the LIN28/Let-7 axis and inhibits glycolytic metabolism and neurosphere formation in NB and that PET scans may be a meaningful imaging tool to evaluate the therapeutic effects of DFMO treatment.
    Oncotarget 11/2014; · 6.63 Impact Factor
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    ABSTRACT: In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease.
    12/2013; 2(1):21. DOI:10.7243/2049-7962-2-21
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    ABSTRACT: Neuroblastoma (NB) is associated with MYCN oncogene amplification occurring in approximately 30% of NBs and is associated with poor prognosis. MYCN is linked to a number of genes including ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. ODC expression is elevated in many forms of cancer including NB. Alpha-difluoromethylornithine (DFMO), an ODC inhibitor, is currently being used in a Phase I clinical trial for treatment of NB. However, cancer cells treated with DFMO may overcome their polyamine depletion by the uptake of polyamines from extracellular sources. A novel polyamine transport inhibitor, AMXT-1501, has not yet been tested in NB. We propose that inhibiting ODC with DFMO, coupled with polyamine transport inhibition by AMXT-1501 will result in enhanced NB growth inhibition. Single and combination drug treatments were conducted on three NB cell lines. DFMO IC50 values ranged from 20.76 to 33.3 mM, and AMXT-1501 IC50 values ranged from 14.13 to 17.72 µM in NB. The combination treatment resulted in hypophosphorylation of retinoblastoma protein (Rb), suggesting growth inhibition via G1 cell cycle arrest. Increased expression of cleaved PARP and cleaved caspase 3 in combination-treated cells starting at 48 hours suggested apoptosis. The combination treatment depleted intracellular polyamine pools and decreased intracellular ATP, further verifying growth inhibition. Given the current lack of effective therapies for relapsed/refractory NB patients and the preclinical effectiveness of DFMO with AMXT-1501, this combination treatment provides promising preclinical results. DFMO and AMXT-1501 may be a potential new therapy for children with NB. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2013; 133(6). DOI:10.1002/ijc.28139 · 6.20 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):LB-160-LB-160. DOI:10.1158/1538-7445.AM2013-LB-160 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):LB-179-LB-179. DOI:10.1158/1538-7445.AM2013-LB-179 · 9.28 Impact Factor
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    ABSTRACT: Current therapeutic options for recurrent neuroblastoma have poor outcomes that warrant the development of novel therapeutic strategies. Specificity protein (Sp) transcription factors regulate several genes involved in cell proliferation, survival, and angiogenesis. Sp1 regulates genes believed to be important determinants of the biological behavior of neuroblastoma. Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, is known to induce the degradation of Sp proteins and may serve as a novel anti-cancer agent. The objective of this investigation was to examine the anti-cancer activity of TA using established human neuroblastoma cell lines. We tested the anti-proliferative effect of TA using SH-SY5Y, CHLA90, LA1 55n, SHEP, Be2c, CMP 13Y, and SMS KCNR cell lines. Cells were treated with TA (0/25/50/100 µM) and cell viability was measured at 24, 48, and 72 h post-treatment. Selected neuroblastoma cell lines were treated with 50 µM TA for 24 and 48 h and tested for cell apoptosis using Annexin-V staining. Caspase activity was measured with caspase 3/7 Glo kit. Cell lysates were prepared and the expression of Sp1, survivin, and c-PARP were evaluated through Western blot analysis. TA significantly inhibited the growth of neuroblastoma cells in a dose/time-dependent manner and significantly decreased Sp1 and survivin expression. Apart from cell cycle (G0/G1) arrest, TA caused significant increase in the apoptotic cell population, caspase 3/7 activity, and c-PARP expression. These results show that TA effectively inhibits neuroblastoma cell growth potentially through suppressing mitosis, Sp1, and survivin expression, and inducing apoptosis. These results show TA as a novel therapeutic agent for neuroblastoma. © 2011 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 05/2013; 52(5). DOI:10.1002/mc.21866 · 4.27 Impact Factor
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    ABSTRACT: Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recur- rent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment de- cisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality con- trol, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predict- tion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor re- view within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expres- sion data and its analysis (3 - 7 days), reports which linked this data into medically actionable drug candidates (1 - 5 days), molecular tumor board (1 - 3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit.
    Journal of Cancer Therapy 10/2012; 3(5):602-612. DOI:10.4236/jct.2012.35077
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    ABSTRACT: Antibodies are important drugs for treating cancer and there is strong rationale for using multiple antibodies to improve outcomes. We labeled two breast cancer binding antibodies, anti-ErbB2 and anti-EpCAM, with infrared fluorescence dyes of different wavelengths and determined their in vivo distribution in a breast cancer xenograft model using a near-infrared (NIR) fluorescence imaging system. Our data show that these two antibodies can be readily assessed simultaneously in mouse xenograft model. This will help guide design of dosing strategies for multiple antibodies and identify potential interaction that could affect pharmacokinetics and possible side effects.
    BioTechniques 04/2012; DOI:10.2144/000113855 · 2.40 Impact Factor
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    ABSTRACT: Purpose: Outcomes in children with neuroblastoma (NB) have steadily improved in developed nations, however, 85% of the world’s children live in low-income countries (LIC); where significant challenges remain. Literature reviews report wide global differences in treatment strategies for neuroblastoma. Project aims: 1. Establish a web-based tumor board (WTB) facilitating clinicians in LIC to discuss challenging patients with neuroblastoma in real time. 2. Assess the needs/limitations of care for children in LIC. 3. Foster global dialogue & collaboration to help develop clinical standards and research in LIC. Method: A monthly, WTB was set up using the platform. Participating institutions present their patients for discussion. Patient demographics, diagnostic evaluations, pathology review, initial treatment considerations, alteration in management based on WTB discussions, resource limitations, and prospective follow-ups are recorded. Results: Within our first year, participation has increased from 7 to 62 members, from 25 countries. To date, 15 cases have been presented. Median participation/conference was 10. In 60% of cases no N-MYC data was available. Additional challenges identified were: infrastructure limitations for supportive care, nutrition support, and treatment options due to cost/availability of medications. Collaborative discussions regarding research projects have begun via this forum. Conclusion: To date, we are able to show that a multidisciplinary WTB has resulted in refining treatment plans for numerous patients with NB. We are prospectively identifying limitations in specific low-income locales and have initiated dialogue to plan research projects in an international setting. A developing project in India will standardize testing for N-MYC amplification and provide treatment guidelines based on this critical risk factor. Future plans include working with SIOP-PODC in developing graduated intensity treatment guidelines for low/intermediate and high risk NB in LIC.
  • Cancer Research 07/2011; 71(8 Supplement):3942-3942. DOI:10.1158/1538-7445.AM2011-3942 · 9.28 Impact Factor
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    ABSTRACT: Patients diagnosed with high-risk neuroblastoma (NB), an extracranial solid tumor in children, have metastases and low survival (30%) despite aggressive multi-modal therapy. Therefore new therapies are urgently needed. We show significant in vitro and in vivo antitumor efficacy of RKS262 in NB. RKS262 showed superior cytotoxicity (IC(50) = 6-25 μM) against six representative NB cell lines compared to its parent analog Nifurtimox (currently in phase 2). Pre-formulated RKS262 (150 mg/kg/daily) pellets administered orally, suppressed tumor growth (60%, p = 0.021) in NB xenograft mice within 28 days. RKS262-treated SMSKCNR cells showed TUNEL-positive DNA nicks and activation of ROS, MAPKs (SAPK/JNK), caspase-3, and p53, along with suppression of the IGF-1R/PI3K/PKC pathway and the Bcl2 family of proteins. RKS262 caused G(2)/M-phase arrest and suppressed cdc-2, cyclin B1, p21, and cyclin D1/D4 expression. N-acetyl-cysteine (NAC; 10 mM) pre-treatment rescued cell viability of RKS262 (23 µM)-treated SMSKCNR cells, and pre-treatment with ascorbic acid (100 μM) and a MAPK inhibitor SB203580 (20 μM) reversed SAPK/JNK, caspase-3 activation, PARP-1 cleavage, and suppression of IGF-1R, PI3K, and PKC phosphorylation. Further, treatment with exogenous BDNF (50 nM) did not suppress SAPK/JNK or ROS activation due to RKS262. Rather, BDNF (50 nM), EGF (100 nM) and IGF-1 (100 nM) co-treatment with RKS262 induced a remarkable S-phase arrest rather than a G(2)/M phase arrest when RKS262 was used alone. In summary, RKS262 shows oral efficacy in NB xenograft animals, and induces apoptosis in vitro in SMSKCNR cells via cell cycle arrest, MAPK and ROS activation, and suppression of IGF-1R/PI3K/PKC and Bcl2 family proteins in a growth factor (BDNF/EGF/IGF-1)-independent fashion.
    Cancer biology & therapy 06/2011; 11(12):1036-45. DOI:10.4161/cbt.11.12.15706 · 3.29 Impact Factor
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    ABSTRACT: Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common brain tumor found in children. We recently showed that nifurtimox induces production of reactive oxygen species (ROS) and subsequent apoptosis in neuroblastoma cells both in vitro and in vivo. Tetrathiomolybdate (TM) has been shown to decrease cell proliferation by inhibition of superoxide dismutase-1 (SOD1). Since both nifurtimox and TM increase ROS levels in cells, we investigated whether the combination of nifurtimox and TM would act synergistically in medulloblastoma cell lines (D283, DAOY). Genome-wide transcriptional analysis, by hybridizing RNA isolated from nifurtimox and TM alone or in combination treated and control cells (D283) on Affymetrix exon array gene chips was carried out to further confirm synergy. We show that nifurtimox and TM alone and in combination decreased cell viability and increased ROS levels synergistically. Examination of cell morphology following drug treatment (nifurtimox + TM) and detection of caspase-3 activation via Western blotting indicated that cell death was primarily due to apoptosis. Microarray data from cells treated with nifurtimox and TM validated the induction of oxidative stress, as many Nrf2 target genes (HMOX1, GCLM, SLC7A11 and SRXN1) (p<10(-5)) were upregulated. Other genes related to apoptosis, oxidative stress, DNA damage, protein folding and nucleosome formation were differentially involved in cells following treatment with nifurtimox + TM. Taken together, our results suggest nifurtimox and TM act synergistically in medulloblastoma cells in vitro, and that this combination warrants further studies as a new treatment for medulloblastoma.
    International Journal of Oncology 03/2011; 38(5):1329-41. DOI:10.3892/ijo.2011.971 · 2.77 Impact Factor
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    ABSTRACT: The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.
    Journal of Pediatric Hematology/Oncology 11/2010; 33(1):25-30. DOI:10.1097/MPH.0b013e3181f47061 · 0.96 Impact Factor
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    ABSTRACT: Bromoacetoxy-calcidiol (B3CD), a pro-apoptotic and cytotoxic agent in neuroblastoma (NB) cell lines, displayed therapeutic potential in vivo as an anticancer drug in a NB xenograft mouse model. Tumors of all animals treated intraperitoneally with B3CD went into regression within 10-30 days of treatment, while tumors in control animals grew aggressively. The response mechanisms of NB cells to B3CD in vitro were studied and included differential targeting of cell cycle key regulators p21 and cyclin D1 on the transcriptional and expression level leading to arrest in G0/G1 phase. In contrast to the effect in ovarian cancer cells, B3CD-induced cell death in SMS-KCNR NB cells was only marginally mediated by the p38 MAPK signaling pathway. Signaling induced by exogenous recombinant EGF leads to a partial restoration of the negative effects of B3CD on SMS-KCNR cell proliferation and survival. Upon combinational treatment of SMS-KCNR cells with B3CD and recombinant EGF, the EGF receptor (EGF-R) was highly activated. We suggest future studies to include analysis of the effects of B3CD in combination therapy with pharmacological inhibitors of cell cycle regulators or with EGF-R-targeting inhibitors, -toxins or -antibodies in vitro and their translation into in vivo models of tumor development.
    Chemical Biology &amp Drug Design 08/2010; 76(2):164-73. DOI:10.1111/j.1747-0285.2010.00988.x · 2.51 Impact Factor
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    ABSTRACT: Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant, and radiation, long-term survival remains at 30% and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA1-55n, LA-N2, SMS-KCNR, and SY5Y was examined. Nifurtimox decreased cell viability in a concentration-dependent manner. Cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay, and caspase-3 activation indicate that cell death was primarily due to apoptosis. Nifurtimox also suppressed basal and TrkB-mediated Akt phosphorylation, and the cytotoxicity of nifurtimox was attenuated by a tyrosine hydroxylase inhibitor (alpha-methyl-tyrosine). Nifurtimox killed catecholaminergic, but not cholinergic, autonomic neurons in culture. In vivo xenograft models showed inhibition of tumor growth with a histologic decrease in proliferation and increase in apoptosis. These results suggest that nifurtimox induces cell death in neuroblastoma. Therefore, further studies are warranted to develop nifurtimox as a promising new treatment for neuroblastoma.
    Journal of Pediatric Hematology/Oncology 04/2009; 31(3):187-93. DOI:10.1097/MPH.0b013e3181984d91 · 0.96 Impact Factor
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    ABSTRACT: Several indole ethyl isothiocyanate (IEITC) analogs were designed, synthesized, and screened to evaluate their cytotoxicity against neuroblastoma (NB) cells in-vitro. In NB, predominantly a tumor of early childhood, survival remains low despite aggressive treatments. Therefore, novel treatment strategies are greatly needed. The objective of the present study was to study the therapeutic potential of IEITC by analyzing the cytotoxic, anti-proliferative, and apoptotic effects on NB cell lines. 7-Methyl-indole-3-ethyl isothiocyanate (7Me-IEITC) proved to be cytotoxic to various NB cell lines (SMS-KCNR, SK-N-SH, SH-SY5Y, and IMR-32) with an IC(50) at 2.5-5.0 microM, while primary control cells (lung fibroblasts) were not affected. 7Me-IEITC led to the activation of apoptotic markers caspase-3, -8, and -9, caused activation of pro-apoptotic p38 MAPK and SAP/JNK, and down-regulated pro-survival factor AKT in SMS-KCNR cells. Moreover, 7Me-IEITC displayed anti-proliferative effects (IC(50) at 600 nM) and caused an arrest in cell cycle progression. This wide effect of 7Me-IEITC on NB cell signaling and survival suggests that it could be developed as a therapeutic agent against neuroblastoma.
    Bioorganic & Medicinal Chemistry Letters 12/2007; 17(21):5846-52. DOI:10.1016/j.bmcl.2007.08.032 · 2.33 Impact Factor
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    ABSTRACT: The cytotoxic, anti-proliferative and apoptotic effects of 3-Bromoacetoxy Calcidiol (B3CD), a derivative of vitamin D3 precursor calcidiol, on human neuroblastoma (NB) cells were examined. NB, predominantly a tumor of early childhood, is the most common extracranial solid tumor. Despite aggressive treatments, survival for advanced stages remains low and novel treatment strategies are needed. B3CD-induced apoptosis in various neuroblastic cells via caspases-3 and -9 activation. B3CD upregulated mitochondrial pro-apoptotic Bax and anti-apoptotic Bcl-2 expression, caused cytochrome c release, downregulated N-Myc expression and activated pro-survival marker Akt. Accordingly, B3CD treatment dose dependently reduced the viability of NB cells with IC50 values between 1 and 3 microm. The cytotoxicity of B3CD was significantly higher than for the calcemic parent-compound vitamin D3 (IC50 between 10 and 30 microm). Further studies revealed that B3CD treatment inhibits the proliferation of NB cells at low concentrations (IC50 between 30 and 100 nm). Cell cycle analysis showed a dramatic increase in the apoptotic sub-diploidal population along with a cell cycle block. In summary, the present study shows that B3CD is toxic to NB cells via suppression of cell proliferation and cell viability by caspase activation and regulation of survival signals. These results suggest that B3CD could be developed as a treatment for NB.
    Chemical Biology &amp Drug Design 11/2007; 70(4):302-10. DOI:10.1111/j.1747-0285.2007.00567.x · 2.51 Impact Factor
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    Jennifer A Straub, Giselle L Saulnier Sholler, Rae Nishi
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    ABSTRACT: Nerve growth factor and neurotrophin-3 are involved in the development of sympathetic neurons; however, whether brain derived neurotrophic factor also plays a role is not known. The purpose of this study was to determine whether BDNF and its receptor, TrkB, are expressed during the development of paravertebral sympathetic ganglia in vivo and to determine the effect of BDNF in vitro. As neural crest cells coalesce to form sympathetic ganglia, TrkB-positive cells are seen in both chicken and mouse embryos. In chicken embryos, TrkB-expressing cells first appear at Hamburger-Hamilton Stage (St) 27 and they co-express HNK-1, confirming that they are migrating neural crest cells. The TrkB-positive cells lack neural markers at this stage; however, they migrate with other neurally differentiating cells that are TrkA and TrkC-positive. By St. 29/30, TrkB-positive cells begin to express the neural specific markers Hu C/D and Islet-1; eventually, all TrkB positive cells commence neural differentiation. By St. 34, TrkB and TrkC staining are lost. BDNF transcript expression parallels that of TrkB. In the mouse, TrkB-positive cells surround newly formed sympathetic ganglia and a small number of TrkB positive cells that co-express tyrosine hydroxylase are seen within ganglia between E13.5-15. In cell culture, many cells from St. 29-30 chicken lumbar sympathetic ganglia express neural markers and are dividing, indicating that they are sympathoblasts. Sympathoblasts and neurons require both nerve growth factor and neurotrophin-3 for survival. BDNF increases the number of cells expressing neural markers in culture by increasing number of cells that incorporate bromodeoxyuridine. In contrast, most TrkB-positive sympathetic cells in vivo are not actively proliferating between E6-E8. Developing paravertebral sympathetic ganglia in avian and murine embryos contain a subpopulation of sympathoblasts that transiently express TrkB and ultimately commence neuronal differentiation. These TrkB expressing sympathoblasts are not actively dividing in vivo; yet, when placed in vitro, will divide in response to BDNF. This suggests that the availability of BDNF in vivo fails to reach a threshold necessary to induce proliferation. We suggest that excess TrkB stimulation of sympathoblasts in vivo may lead to the genesis of neuroblastoma.
    BMC Developmental Biology 02/2007; 7:10. DOI:10.1186/1471-213X-7-10 · 2.75 Impact Factor
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    ABSTRACT: Chemotherapy-resistant neuroblastoma is a difficult disease to treat with poor survival. We treated a patient with neuroblastoma who had progressed on conventional chemotherapy. This 5-year-old girl with chemotherapy-resistant neuroblastoma developed Chagas disease at the start of salvage chemotherapy for which she was also started on nifurtimox. The neuroblastoma response to these treatments resulted in clinical remission. In vitro, treatment of a neuroblastoma cell line with nifurtimox resulted in decreased cell viability whereas no effect was seen on an endothelial cell line. Nifurtimox shows promise as a potential new treatment for neuroblastoma and warrants further testing.
    Journal of Pediatric Hematology/Oncology 11/2006; 28(10):693-5. DOI:10.1097/01.mph.0000212994.56812.f2 · 0.96 Impact Factor

Publication Stats

110 Citations
66.37 Total Impact Points


  • 2013–2015
    • Helen DeVos Children's Hospital
      Grand Rapids, Michigan, United States
    • Van Andel Research Institute
      Grand Rapids, Michigan, United States
  • 2011
    • Alpert Medical School - Brown University
      • Department of Obstetrics and Gynecology
      Providence, RI, United States
  • 2006–2010
    • University of Vermont
      • Department of Pediatrics
      Burlington, Vermont, United States