St Jude Children Research Hospital

Memphis, TN, United States

St Jude Children Research Hospital

Memphis, TN, United States
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Santiago T.,St Jude Children Research Hospital | Clay M.R.,St Jude Children Research Hospital | Allen S.J.,St Jude Children Research Hospital | Orr B.A.,St Jude Children Research Hospital
Modern Pathology | Year: 2017

Primitive myxoid mesenchymal tumor of infancy is a rare sarcoma that preferentially affects infants. It can be locally aggressive and rarely metastasizes, but the long-term outcome of children with this tumor is mostly unknown. Histologically, it is characterized by primitive cells with abundant myxoid stroma. Internal tandem duplication of B-cell CLL/lymphoma 6 (BCL6)-interacting co-repressor (BCOR) exon 15 has recently been described in clear cell sarcoma of kidney, central nervous system high-grade neuroepithelial tumor with BCOR alteration, and primitive myxoid mesenchymal tumor of infancy. Herein, we report five cases of primitive myxoid mesenchymal tumor of infancy: three girls and two boys with mean age of 6.5 months. The tumors were located in the paraspinal region (n=3), back (n=1), or foot (n=1) and ranged in size from 2.5 to 10.2 cm. BCOR internal tandem duplication was confirmed by PCR and sequencing in all five cases. The minimally duplicated region consisted of nine residues, which is shorter than was previously reported in other BCOR-associated tumors. To assess the clinical value and specificity of the BCOR internal tandem duplication, a group of 11 ETV6-rearranged congenital infantile fibrosarcomas were evaluated and no BCOR internal tandem duplication was identified in any case. Though not detected in congenital infantile fibrosarcomas, BCOR and BCL6 immunoreactivity was present in >90% of the nuclei of tumor cells in each of the five primitive myxoid mesenchymal tumor of infancy. The presence of BCOR internal tandem duplication in all five primitive myxoid mesenchymal tumors of infancy provides evidence that it is a recurrent somatic abnormality and substantiates the concept that this tumor is a unique sarcoma of infancy. Our findings indicate that identification of BCOR internal tandem duplication and/or nuclear immunoreactivity for BCOR or BCL6 can aid in the diagnosis of primitive myxoid mesenchymal tumor of infancy and help to differentiate it from congenital infantile fibrosarcoma.Modern Pathology advance online publication, 3 March 2017; doi:10.1038/modpathol.2017.12. © 2017 United States & Canadian Academy of Pathology USCAP, Inc

Tanzeem S.,East West University of Bangladesh | Reddick W.E.,St Jude Children Research Hospital | Iftekharuddin K.M.,Old Dominion University
8th International Conference on Electrical and Computer Engineering: Advancing Technology for a Better Tomorrow, ICECE 2014 | Year: 2015

The focus of this work was to develop a 3D mapping of brain tumor (glioma) growth based on cell proliferation and diffusion. In this mathematical model, we incorporated high resolution brain tissue maps (white and gray matter) from an anonymized pediatric patient and initialized the model with a single voxel seed point of tumor with a Gaussian distribution. We used this model to investigate the ratio of growth rate to the diffusion coefficient (ρ/D) which determines the proportion of tumor that is detectable. After expansion of the tumor growth model to three dimensions and solving the differential equations for our specific starting conditions, we performed several simulations to assess tumor growth patterns. After observing the performance of the model at varying time points across a one year time frame with different values for ρ/D, we ascertained that the tumor diffused more rapidly than the cell proliferated for a short period of time followed by an exponential growth in detectable tumor size. © 2014 IEEE.

PubMed | Seattle Childrens Hospital, Center for Neuroscience and Behavioral Medicine, Northeast Ohio Medical University, Ohio State University and 8 more.
Type: Clinical Trial, Phase I | Journal: Pediatric neurology | Year: 2015

The primary goals of the Childrens Cancer Group 99703 study were to assess the feasibility and tolerability of-as well as the response rate to-a novel dose-intensive chemotherapy regimen.Between March 1998 and October 2004, 92 eligible patients were enrolled. Following biopsy/resection, patients received three identical cycles of Induction chemotherapy (vincristine, cyclophosphamide, etoposide, and cisplatin) administered every 21-28days. Patients without tumor progression then received three consolidation cycles of marrow-ablative chemotherapy (thiotepa and carboplatin) followed by autologous hematopoietic cell rescue.The maximum tolerated dose of thiotepa was 10mg/kg/day 2days per cycle. The toxic mortality rate was zero during induction and 2.6% during consolidation. Centrally evaluated response rates to induction and consolidation in evaluable patients with residual tumor were 73.3% and 66.7%, respectively. Disease progression rates on induction and consolidation were 4%. Five-year event-free survival and overall survival were 43.95.2% and 63.65% respectively. Gross total resection versusless than gross total resection were the only significant outcome comparisons: 5-year maximum tolerated dose and overall survival of 54.47% versus 28.97% (P=0.0065) and 75.98% versus 48.78% (P=0.0034), respectively. The 5-year maximum tolerated dose for localized (M0) versus metastatic (M1+) medulloblastoma was 67.5 9.5% versus 30 14.5% (P=0.007). The 5-year maximum tolerated dose and overall survival for desmoplastic medulloblastoma patients versus other medulloblastoma were 78.6 11% versus 50.5 12% (P=0.038) and 85.7 9.4% versus 60.611.6% (P=0.046), respectively.This phase I dose-escalation study of marrow-ablative thiotepa regimen determined a maximum tolerated dose that had acceptable toxicity. Overall survival data justify this strategy for current Childrens Oncology Group studies.

Kahlert U.D.,Johns Hopkins Hospital | Kahlert U.D.,University Medical Center Dusseldorf | Suwala A.K.,University Medical Center Dusseldorf | Koch K.,University Medical Center Dusseldorf | And 5 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2015

Wingless (Wnt) signaling is an important pathway in gliomagenesis and in the growth of stem-like glioma cells. Using immunohistochemistry to assess the translocation of β-catenin protein, we identified intranuclear staining suggesting Wnt pathway activation in 8 of 43 surgical samples (19%) from adult patients with glioblastoma and in 9 of 30 surgical samples (30%) from pediatric patients with glioblastoma. Wnt activity, evidenced by nuclear β-catenin in our cohort and high expression of its target AXIN2 (axis inhibitor protein 2) in published glioma datasets, was associated with shorter patient survival, although this was not statistically significant. We determined the effects of the porcupine inhibitor LGK974 on 3 glioblastoma cell lines with elevated AXIN2 and found that it reduced Wnt pathway activity by 50% or more, as assessed by T-cell factor luciferase reporters. Wnt inhibition led to suppression of growth, proliferation in cultures, and modest induction of cell death. LGK974 reduced NANOG messenger RNA levels and the fraction of cells expressing the stem cell marker CD133 in neurosphere cultures, induced glial differentiation, and suppressed clonogenicity. These data indicate that LGK974 is a promising new agent that can inhibit the canonical Wnt pathway in vitro, slow tumor growth, and deplete stem-like clonogenic cells, thereby providing further support for targeting Wnt in patients with glioblastoma. Copyright © 2015 by the American Association of Neuropathologists, Inc.

Kahlert U.D.,Johns Hopkins Hospital | Kahlert U.D.,University Medical Center Dusseldorf | Suwala A.K.,University Medical Center Dusseldorf | Raabe E.H.,Johns Hopkins Hospital | And 6 more authors.
Brain Pathology | Year: 2015

Diffuse spread through brain parenchyma and the presence of hypoxic foci rimmed by neoplastic cells are two cardinal features of glioblastoma, and low oxygen is thought to drive movement of malignant gliomas in the core of the lesions. Transcription factors associated with epithelial-to-mesenchymal transition (EMT) have been linked to this invasion, and we found that hypoxia increased in vitro invasion up to fourfold in glioblastoma neurosphere lines and induced the expression of ZEB1. Immunohistochemical assessment of 295 surgical specimens consisting of various types of pediatric and adult brain cancers showed that ZEB1 expression was significantly higher in infiltrative lesions than less invasive tumors such as pilocytic astrocytoma and ependymoma. ZEB1 protein was also present in human fetal periventricular stem and progenitor cells and ZEB1 inhibition impaired migration of in vitro propagated human neural stem cells. The induction of ZEB1 protein in hypoxic glioblastoma neurospheres could be partially blocked by the HIF1alpha inhibitor digoxin. Targeting ZEB1 blocked hypoxia-augmented invasion of glioblastoma cells in addition to slowing them in normoxia. These data support the role for ZEB1 in invasive and high-grade brain tumors and suggest its key role in promoting invasion in the hypoxic tumor core as well as in the periphery. © 2014 International Society of Neuropathology.

PubMed | Charité - Medical University of Berlin, The University of Auckland, Ludwig Maximilians University of Munich, University Hospital Schleswig Holstein Campus Kiel and 2 more.
Type: | Journal: Haematologica | Year: 2016

Philadelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult B-cell precursor ALL (BCP-ALL) patients (median age: 42 years) were classified as Ph-like using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and MLL rearrangements. IGH-CRLF2 rearrangements (6/16; p=0.002) and mutations in JAK2 (7/16; p<0.001) were exclusively found in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated on German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% for Ph-like (n=19) and patients negative for BCR-ABL1-, MLL-rearrangements and the Ph-like subtype (remaining BCP-ALL, n=40). Significantly fewer Ph-like ALL patients reached molecular complete remission (33% vs 79%; p=0.01) and had a lower probability of continuous complete remission (24% vs 62%; p<0.001) and overall survival (22% vs 64%; p=0.006) at 5 years compared to remaining BCP-ALL patients. The profile of genetic lesions in adult Ph-like ALL, including older adults, resembles pediatric Ph-like ALL and differs from remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed. (NCT00199056, NCT00198991).

Teng B.,West Virginia University | Smith J.D.,Cleveland Clinic | Rosenfeld M.E.,University of Washington | Robinet P.,Cleveland Clinic | And 3 more authors.
Cardiovascular Research | Year: 2014

AimsThe goal of this study was to determine whether the A1 adenosine receptor (AR) plays a role in atherosclerosis development and to explore its potential mechanisms.Methods and resultsDouble knockout (DKO) mice, deficient in the genes encoding A1 AR and apolipoprotein E (apoE), demonstrated reduced atherosclerotic lesions in aortic arch (en face), aortic root, and innominate arteries when compared with apoE-deficient mice (APOE-KO) of the same age. Treating APOE-KO with an A1 AR antagonist (DPCPX) also led to a concentration-dependent reduction in lesions. The total plasma cholesterol and triglyceride levels were not different between DKO and APOE-KO; however, higher triglyceride was observed in DKO fed a high-fat diet. DKO also had higher body weights than APOE-KO. Plasma cytokine concentrations (IL-5, IL-6, and IL-13) were significantly lower in DKO. Proliferating cell nuclear antigen expression was also significantly reduced in the aorta from DKO. Despite smaller lesions in DKO, the composition of the innominate artery lesion and cholesterol loading and efflux from bone marrow-derived macrophages of DKO were not different from APOE-KO.ConclusionThe A1 AR may play a role in the development of atherosclerosis, possibly due to its pro-inflammatory and mitogenic properties. © 2014 The Author.

Luo M.,Hefei University of Technology | Yan B.,St Jude Children Research Hospital | Yan B.,Shandong University
Tetrahedron Letters | Year: 2010

A series of novel N-metal complexes containing chiral α-ethylphenyl amines was synthesized and they catalyzed asymmetric Henry reactions affording products with high enantioselectivity. © 2010 Elsevier Ltd. All rights reserved.

PubMed | St Jude Children Research Hospital
Type: Comment | Journal: Blood | Year: 2015

In this issue of Blood, Brousseau et al report results from the Magnesium for Children in Crisis (MAGiC; #NCT01197417) trial. This multicenter, double-blind, placebo-controlled trial compared the effects of intravenous magnesium to saline in children with sickle cell anemia (SCA) admitted to the hospital for acute vaso-occlusive pain (VOC). Although magnesium was found to be ineffective, MAGiC illustrates an effective strategy for rapid and efficient patient accrual in pediatric SCA studies.

PubMed | St Jude Children Research Hospital
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2015

Subcellular fractionation is a valuable procedure in cell biology to separate and purify various subcellular constituents from one another, i.e., nucleus, cytosol, membranes/organelles, and cytoskeleton. The procedure relies on the use of differential centrifugation of cell and tissue homogenates, but additional purification steps now permit the isolation of inter-organellar membrane contact sites. Here, we outline a protocol tailored for the isolation of mitochondria, mitochondria-associated ER membranes (MAMs) and glycosphingolipid-enriched microdomains (GEMs) from the adult mouse brain, primary neurospheres, and murine embryonic fibroblasts (MEFs).

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