4.

Object Chordoma is a malignant bone neoplasm hypothesized to arise from notochordal remnants along the length of the neuraxis. Recent genomic investigation of chordomas has identified T (Brachyury) gene duplication as a major susceptibility mutation in familial chordomas. Brachyury plays a vital role during embryonic development of the notochord and has recently been shown to regulate epithelial-to-mesenchymal transition in epithelial-derived cancers. However, current understanding of the role of this transcription factor in chordoma is limited due to the lack of availability of a fully characterized chordoma cell line expressing Brachyury. Thus, the objective of this study was to establish the first fully characterized primary chordoma cell line expressing gain of the T gene locus that readily recapitulates the original parental tumor phenotype in vitro and in vivo. Methods Using an intraoperatively obtained tumor sample from a 61-year-old woman with primary sacral chordoma, a chordoma cell line (JHC7, or Johns Hopkins Chordoma Line 7) was established. Molecular characterization of the primary tumor and cell line was conducted using standard immunostaining and Western blotting. Chromosomal aberrations and genomic amplification of the T gene in this cell line were determined. Using this cell line, a xenograft model was established and the histopathological analysis of the tumor was performed. Silencing of Brachyury and changes in gene expression were assessed. Results The authors report, for the first time, the successful establishment of a chordoma cell line (JHC7) from a patient with pathologically confirmed sacral chordoma. This cell line readily forms tumors in immunodeficient mice that recapitulate the parental tumor phenotype with conserved histological features consistent with the parental tumor. Furthermore, it is demonstrated for the first time that silencing of Brachyury using short hairpin RNA renders the morphology of chordoma cells to a more differentiated-like state and leads to complete growth arrest and senescence with an inability to be passaged serially in vitro. Conclusions This report represents the first xenograft model of a sacral chordoma line described in the literature and the first cell line established with stable Brachyury expression. The authors propose that Brachyury is an attractive therapeutic target in chordoma and that JHC7 will serve as a clinically relevant model for the study of this disease.

We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.

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In addition to stem cells providing a better understanding about the biology and origins of gliomas, new therapeutic approaches have been developed based on the use of stem cells as delivery vehicles. The unique ability of stem cells to track down tumor cells makes them a very appealing therapeutic modality. This review introduces neural and mesenchymal stem cells, discusses the advances that have been made in the utilization of these stem cells as therapies and in diagnostic imaging (to track the advancement of the stem cells towards the tumor cells), and concludes by addressing various challenges and concerns regarding these therapies. Keywords brain tumor; glioma; mesenchymal stem cell; neural stem cell; stem cell Despite the large amount of research that has been carried out investigating the biology and treatment of gliomas, the median survival is still 1 year or less for glioblastoma multiforme (GBM) and approximately 3 years for anaplastic astrocytoma [1][2][3][4][5]. High-grade gliomas have the ability to infiltrate local structures and migrate long distances, even to the contralateral hemisphere, leading to disease recurrence despite aggressive resection [6][7][8][9][10]. Even after seemingly curative resection of the tumor, there are often microsatellites of tumor cells scattered throughout normal brain tissue that have the potential to continue proliferating and cause tumor recurrence in other areas of the brain [8,10,11]. Moreover, tumor infiltration of eloquent areas of the brain often limits the extent of tumor resection [5,9,10,[12][13][14]. In the 1930s, Walter Dandy reported recurrence of contralateral gliomas even after hemispher ectomy [15]. Radiotherapy [16,17 and chemotherapy [3,18,19] have had limited success in treating gliomas [2,3]. Both are limited by their toxicity to normal brain tissue that could lead to further brain damage and decreased quality of life for patients [20][21][22]. Moreover, the effect of chemo therapy is often suboptimal because there is limited drug penetration across the blood-brain The resemblance of the properties and attributes of stem cells to those of BTSCs has initiated interest in how stem cells can be armed to track and eradicate tumors [29,41,42]. In this review, we will discuss the tropism of stem cells for tumors, review the advances in neural and mesenchymal stem cell (MSC) therapies for gliomas, and finally outline the concerns and challenges in making stem cells into a treatment modality in humans. Stem cell tropism for tumorsOne of the remarkable properties of both NSCs and MSCs is their tropism for tumor cells [29,43]. These stem cells have the ability to migrate across the blood-brain barrier into the tumor when administered intra-arterially [29,44] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIt is noteworthy to discuss the CXCR4-SDF-1α interaction, which plays an important role in inflammation, tumor tropism of stem cells and the pathology of gliomas [64][65][66]. The chemokine receptor CXCR4 has been found t...

Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis.

African Americans and Hispanics have disproportionately worse access to high-quality neuro-oncologic care over time compared with whites. Higher countywide median household income and decreased countywide poverty rate were associated with better access to high-volume hospitals, implicating socioeconomic factors in predicting admission to high-quality centers.

Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi). Here, we show that non-hydrolyzable analogues of PPi, bisphosphonates, are potent inhibitors of T. cruzi hexokinase (TcHK). We determined the activity of 42 bisphosphonates against TcHK, and the IC(50) values were used to construct pharmacophore and comparative molecular similarity indices analysis (CoMSIA) models for enzyme inhibition. Both models revealed the importance of electrostatic, hydrophobic, and steric interactions, and the IC(50) values for 17 active compounds were predicted with an average error of 2.4x by using the CoMSIA models. The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi.