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  • 1
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    {beta}-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas [Cell Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-05-02
    Description: Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin-catenin complexes at the cell membrane leading to nuclear translocation of β-catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active—but dysregulated—in astrocytomas. Inhibition of β-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    TIC-Specific Aptamers (2013)
    The American Association for Cancer Research (AACR)
    Details
    Publication Date: 2013-08-02
    Description: Glioblastomas display cellular hierarchies with self-renewing tumor-initiating cells (TIC), also known as cancer stem cells, at the apex. Although the TIC hypothesis remains controversial and the functional assays to define the TIC phenotype are evolving, we and others have shown that TICs may contribute to therapeutic resistance, tumor spread, and angiogenesis. The identification of TICs has been informed by the use of markers characterized in normal stem cells, but this approach has an inherent limitation to selectively identify TICs. To develop reagents that enrich TICs but not matched non-TICs or tissue-specific stem cells, we adopted Cell-Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX) to identify glioblastoma TIC-specific nucleic acid probes—aptamers—that specifically bind TICs. In this study, using Cell-SELEX with positive selection for TICs and negative selection for non-TICs and human neural progenitor cells, we identified TIC aptamers that specifically bind to TICs with excellent dissociation constants (Kd). These aptamers select and internalize into glioblastoma cells that self-renew, proliferate, and initiate tumors. As aptamers can be modified to deliver payloads, aptamers may represent novel agents that could selectively target or facilitate imaging of TICs. Cancer Res; 73(15); 4923–36. ©2013 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 3
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    Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-10
    Description: Background Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood–tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy. Methods Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m 2 ) 2–3 h before surgery or 2–5 doses of lapatinib (1250 mg) daily, the last dose 2–3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry. Results Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19–9.8) was noted for lapatinib BCBM-to-serum ratio. Conclusions This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.
    Print ISSN: 1522-8517
    Electronic ISSN: 1523-5866
    Topics: Medicine
    Published by Oxford University Press on behalf of The Society for Neuro-Oncology (SNO).
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  • 4
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    In Vitro Selection of Neisseria gonorrhoeae Mutants with Elevated MIC Values and Increased Resistance to Cephalosporins [Mechanisms of Resistance] (2014)
    The American Society for Microbiology (ASM)
    Details
    Publication Date: 2014-10-17
    Description: Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third-generation cephalosporins. Here we report the in vitro isolation of two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic penA gene, and the second contains an insertion mutation in pilQ .
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
    Published by The American Society for Microbiology (ASM)
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  • 5
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    Crystal growth experiments in the systems Ni2MSbO6 (M = Sc, In) using chemical vapour transport reactions: Ni2InSbO6 and NiSb2O6 crystals in the millimetre range (2013)
    Wiley-Blackwell
    Details
    Publication Date: 2013-12-24
    Description: Endothermic chemical vapour transport (CVT) reactions of Ni 2 M SbO 6 ( M = Sc, In), using a temperature gradient of 1313 → 1233 K and HgCl 2 , HgBr 2 , PtCl 2 or TeCl 4 as transport agents, led to growth of Ni 2 InSbO 6 single crystals in the millimetre range, whereas in the case of Ni 2 ScSbO 6 an incongruent dissolution of the solid in the source region was observed, leading to the formation of single crystals of the ternary phase NiSb 2 O 6 in the sink region. The crystal structures of the obtained crystals were refined from single crystal X-ray data with high precision [Ni 2 InSbO 6 : R 3, Z = 3, a = 5.21640(10) Å, c = 14.0142(3) Å, 1279 structure factors, 33 parameters, R [ F 2 〉 2 σ ( F 2 )] = 0.0189; NiSb 2 O 6 : P 4 2 / mnm, Z = 2, a = 4.63910(10) Å, c = 9.2182(2) Å, 500 structure factors, 19 parameters, R [ F 2 〉 2 σ ( F 2 )] = 0.0145]. Ni 2 InSbO 6 crystallizes in a corundum-related structure, NiSb 2 O 6 in the trirutile structure type. Spontaneous polarization and the ferroelectric transition temperature were estimated from the atomic arrangement and cation displacement along the polar axis in Ni 2 InSbO 6 . Magnetic measurements on Ni 2 InSbO 6 evidence an antiferromagnetic transition near T N = 74 K, with significant magnetic frustration.
    Print ISSN: 0232-1300
    Electronic ISSN: 1521-4079
    Topics: Geosciences , Physics
    Published by Wiley-Blackwell
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  • 6
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    The molecular biology of WHO grade I astrocytomas (2012)
    Oxford University Press
    Details
    Publication Date: 2012-11-16
    Description: World Health Organization (WHO) grade I astrocytomas include pilocytic astrocytoma (PA) and subependymal giant cell astrocytoma (SEGA). As technologies in pharmacologic neo-adjuvant therapy continue to progress and as molecular characteristics are progressively recognized as potential markers of both clinically significant tumor subtypes and response to therapy, interest in the biology of these tumors has surged. An updated review of the current knowledge of the molecular biology of these tumors is needed. We conducted a Medline search to identify published literature discussing the molecular biology of grade I astrocytomas. We then summarized this literature and discuss it in a logical framework through which the complex biology of these tumors can be clearly understood. A comprehensive review of the molecular biology of WHO grade I astrocytomas is presented. The past several years have seen rapid progress in the level of understanding of PA in particular, but the molecular literature regarding both PA and SEGA remains nebulous, ambiguous, and occasionally contradictory. In this review we provide a comprehensive discussion of the current understanding of the chromosomal, genomic, and epigenomic features of both PA and SEGA and provide a logical framework in which these data can be more readily understood.
    Print ISSN: 1522-8517
    Electronic ISSN: 1523-5866
    Topics: Medicine
    Published by Oxford University Press on behalf of The Society for Neuro-Oncology (SNO).
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  • 7
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    Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity [Research Papers] (2012)
    Cold Spring Harbor Laboratory Press
    Details
    Publication Date: 2012-06-12
    Description: Growth factor-mediated proliferation and self-renewal maintain tissue-specific stem cells and are frequently dysregulated in cancers. Platelet-derived growth factor (PDGF) ligands and receptors (PDGFRs) are commonly overexpressed in gliomas and initiate tumors, as proven in genetically engineered models. While PDGFRα alterations inform intertumoral heterogeneity toward a proneural glioblastoma (GBM) subtype, we interrogated the role of PDGFRs in intratumoral GBM heterogeneity. We found that PDGFRα is expressed only in a subset of GBMs, while PDGFRβ is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs). Genetic or pharmacological targeting of PDGFRβ (but not PDGFRα) attenuated GSC self-renewal, survival, tumor growth, and invasion. PDGFRβ inhibition decreased activation of the cancer stem cell signaling node STAT3, while constitutively active STAT3 rescued the loss of GSC self-renewal caused by PDGFRβ targeting. In silico survival analysis demonstrated that PDGFRB informed poor prognosis, while PDGFRA was a positive prognostic factor. Our results may explain mixed clinical responses of anti-PDGFR-based approaches and suggest the need for integration of models of cancer as an organ system into development of cancer therapies.
    Print ISSN: 0890-9369
    Topics: Biology
    Published by Cold Spring Harbor Laboratory Press
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  • 8
    Electronic Resource
    Electronic Resource
    Ferroelectric properties of Cd1−xZnxTe solid solutions (1993)
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 74 (1993), S. 513-520 
    Details
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Measurements of the spontaneous polarization P, x-ray diffraction, birefringence, dielectric constant at different frequencies, and specific heat Cp of the Cd0.9Zn0.1Te alloy are presented. The results demonstrate that this system exhibits a diffuse, second-order ferroelectric transition. The transition is of order-disorder type as deduced from the dielectric measurements. It is found that: (a) The birefringence is proportional to P, as expected from a system with a piezoelectric paraelectric phase; (b) the heat capacity is given by Cp=(Tc/C)||(PdP/dT)||, where C is the Curie constant. One of the main phenomena observed in these solid solutions is the instability of the ferroelectric phase: Once the neighborhood of the transition temperature is reached, the transition disappears upon subsequent cooling. A hypothesis for this instability is offered in terms of a two-state configuration-coordinate diagram.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.355262
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  • 9
    Electronic Resource
    Electronic Resource
    Hindered transformation of Pd2Ge to PdGe in the Pd/a-Ge:H system (1993)
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 73 (1993), S. 8309-8312 
    Details
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: A comparative study of the interfacial reactions between Pd and a-Ge:H, deposited at TS=150 °C (low temperature, LT) and at TS=200, 300 °C (high temperature, HT), was carried out by x-ray diffraction and Auger electron spectroscopy after sample annealing in the regime of T=200–300 °C and t=1/4–4 h. It was found that the Pd/a-Ge:H(LT) formed a much more stable Pd2Ge interfacial layer, compared to the Pd/a-Ge:H(HT) system in which the Pd2Ge was transformed to PdGe. The main difference between the LT- and the HT-a-Ge:H films is probably the structure of the material. Whereas the HT films are compact, the LT-a-Ge films contain a network of voids which slow down the diffusion of Ge to the interface.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.353449
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  • 10
    Electronic Resource
    Electronic Resource
    Interfacial reactions in the Pd/a-Si/c-Si system (1992)
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 71 (1992), S. 289-295 
    Details
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Auger electron spectroscopy, x-ray diffraction, and transmission electron microscopy (TEM) have been used to study the kinetics and morphology of phase transformations in two-layer structures of Pd/a-Si deposited on silicon substrates. Different kinds of a-Si were used: undoped, hydrogenated-deuterated, and fluorinated (a-Si, a-Si:H:D, and a-Si:F, respectively). It was found that the as-deposited Pd/a-Si interface included an intermixed region with a composition close to Pd2Si, for all samples studied. This region widened during room temperature aging. Heat treatments in the temperature range of 200–400 °C resulted in the formation of an oriented, textured, palladium silicide (Pd2Si). The morphology of the Pd2Si region depended on the thicknesses of the Pd and a-Si films. Fractal-like colonies of the Pd2Si silicide formed in the nonsupported double layer films of Pd/a-Si:F during in situ heat treatment in TEM. The growth of these Pd2Si dendrites had 0.1–1 μm/s velocity and was a diffusion controlled process. Kinetic parameters of the silicidation process were obtained from the x-ray diffraction data. The growth of the crystalline Pd2Si layer in thick films was also found to be controlled by a diffusion limited process with an activation energy of 1.5 eV in all samples. The presence of F in a-Si promoted the formation of Pd2Si both in the room-temperature processes and following heat treatments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.350702
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