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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; TUMOR-CELLS ; TISSUE ; BINDING ; METASTASIS ; EXTRACELLULAR-MATRIX ; ADHESION ; MIGRATION ; INTEGRIN ; MALIGNANCY ; INDEPENDENT PROGNOSTIC MARKER ; BREAST-CARCINOMA CELLS ; INTEGRINS ; FORCE ; CD24 EXPRESSION
    Abstract: The malignancy of a tumor depends on the capability of cancer cells to metastasize. The process of metastasis involves cell invasion through connective tissue and transmigration through endothelial monolayers. The expression of the glycosylphosphatidylinositol- anchored receptor CD24 is increased in several tumor types and is consistently associated with increased metastasis formation in patients. Furthermore, the localization of beta 1-integrins in lipid rafts depends on CD24. Cell invasion is a fundamental biomechanical process and usually requires cell adhesion to the extracellular matrix (ECM) mainly through beta 1 heterodimeric integrin receptors. Here, we studied the invasion of A125 human lung cancer cells with different CD24 expression levels in three-dimensional ECMs. We hypothesized that CD24 expression increases cancer cell invasion through increased contractile forces. To analyze this, A125 cells (CD24 negative) were stably transfected with CD24 and sorted for high and low CD24 expression. The invasiveness of theCD24(high) andCD24(low) transfectants was determined in three-dimensional ECMs. The percentage of invasive cells and their invasion depth was increased in CD24(high) cells compared with CD24(low) cells. Knockdown of CD24 and of the beta 1-integrin subunit in CD24(high) cells decreased their invasiveness, indicating that the increased invasiveness is CD24 and beta 1-integrin subunit-dependent. Fourier transform traction microscopy revealed that the CD24(high) cells generated 5-fold higher contractile forces compared with CD24(low) cells. To analyze whether contractile forces are essential for CD24-facilitated cell invasion, we performed invasion assays in the presence of myosin light chain kinase inhibitor ML-7 as well as Rho kinase inhibitor Y27632. Cell invasiveness was reduced after addition of ML-7 and Y27632 in CD24(high) cells but not in CD24(neg) cells. Moreover, after addition of lysophosphatidic acid or calyculin A, an increase in pre-stress in CD24(neg) cells was observed, which enhanced cellular invasiveness. In addition, inhibition of the Src kinase or STAT3 strongly reduced the invasiveness of CD24(high) cells, slightly reduced that of CD24(low) cells, and did not alter the invasiveness of CD24(neg) cells. Taken together, these results suggest that CD24 enhances cell invasion through increased generation or transmission of contractile forces
    Type of Publication: Journal article published
    PubMed ID: 21828044
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  • 2
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; VITRO ; DISEASE ; RISK ; GENE ; PROTEIN ; validation ; PATIENT ; DNA ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; BREAST ; BREAST-CANCER ; TRIAL ; CARCINOMA CELLS ; OVARIAN-CANCER ; SNP ; PCR ; PROGNOSTIC-FACTORS ; PROGNOSTIC FACTORS ; P-SELECTIN ; POOR-PROGNOSIS ; MULTIPLE-SCLEROSIS ; PATIENT SURVIVAL ; AUTOIMMUNE-DISEASES ; PROGNOSTIC MARKER ; NEOADJUVANT CHEMOTHERAPY ; AUTOREACTIVE T-CELLS ; pathologic complete response ; primary breast cancer ; LYMPHOCYTE ; ANTICANCER CHEMOTHERAPY ; Predictive marker
    Abstract: Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor-positive subgroup. There was no correlation between CD24 3'UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.
    Type of Publication: Journal article published
    PubMed ID: 21960110
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  • 3
    Keywords: EXPRESSION ; PROGRESSION ; CARCINOMA-CELLS ; P-SELECTIN ; CD24 ; HEAT-STABLE ANTIGEN ; PROTEIN-TYROSINE KINASES ; OVARIAN-CARCINOMA ; BREAST-CANCER CELLS ; cell invasion ; therapeutic antibodies ; C-SRC ; GENE CD24 ; Lipid-rafts
    Abstract: CD24 is a glycosyl-phosphatidylinositol-anchored protein with mucin-type structure that resides exclusively in membrane microdomains. CD24 is often highly expressed in carcinomas and correlates with poor prognosis. Experimentally, the over-expression or depletion of CD24 alters cell proliferation, adhesion, and invasion in vitro and tumor growth in vivo. However, little is known about the mechanisms by which CD24 mediates these cellular effects. Here we have studied the mechanism of CD24-dependent cell invasion using transient CD24 knock-down or over-expression in human cancer cell lines. We show that CD24 depletion reduced tumor cell invasion and up-regulated expression of Tissue Factor Pathway Inhibitor 2 (TFPI-2), a potent inhibitor of extracellular matrix degradation that can block metastases formation and tumor cell invasion. Over-expression of CD24 in A125 cells resulted in reduced TFPI-2 expression and enhanced invasion. We provide evidence that the activity of c-Src is reduced upon CD24 knock-down. The silencing of c-Src, similar to CD24, was able to enhance TFPI-2 expression and reduce tumor cell invasion. An inverse expression of CD24 and TFPI-2 was observed by immunohistochemical analysis of primary breast cancers (N = 1,174). TFPI-2 expression was highest in CD24 negative samples and lowered with increasing CD24 expression. Patients with a CD24 low/TFPI-2 high phenotype showed significantly better survival compared to CD24 high/TFPI-2 low patients. Our results provide evidence that CD24 can regulate cell invasion via TFPI-2 and suggests a role of c-Src in this process.
    Type of Publication: Journal article published
    PubMed ID: 21984372
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  • 4
    Abstract: CD24 is a small, highly glycosylated cell surface protein that is linked to the membrane through a glycosyl-phosphatidylinositol anchor. It is overexpressed in many human carcinomas and its expression is linked to bad prognosis. Lately, lack or low expression of CD24 was used to identify tumor stem cells resulting in conflicting data on the usefulness of this marker. In many immunohistochemical studies, the mAb SN3b was used but the epitope and specificity of this antibody have never been thoroughly investigated. In other studies based mainly on cytofluorographic analysis, the mAb ML-5 was applied. In this study, we compared the epitope of mAb SN3b to the CD24 mAbs SWA-11 and ML-5 that both bind to the core protein of CD24. Using tissue microarrays and affinity-purified CD24 glycoforms, we observed only a partial overlap of SN3b and SWA11 reactivity. The mAb SN3b recognizes sialic acid most likely on O-linked glycans that can occur independently of the CD24 protein backbone. The SN3b epitope was not related to common sialylated cancer-associated glycan structures. Both SN3b epitope positive or negative CD24 glycoforms supported the binding of P-selectin and Siglec-5. In breast cancer, the SN3b reactivity was associated with bad prognosis, whereas SWA11 was not. In renal cell cancer, the SN3b epitope was completely absent but SWA11 reactivity was a prognostic factor. Our results shed new light on the tumorbiological role of CD24 and resolve discrepancies in the literature related to the use of different CD24 mAbs.
    Type of Publication: Journal article published
    PubMed ID: 20351695
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  • 5
    ISSN: 1089-7623
    Source: AIP Digital Archive
    Topics: Physics , Electrical Engineering, Measurement and Control Technology
    Notes: A design using a backscattering geometry is presented, which emphasizes high sensitivity and high spatial resolution at the outer edge of the National Spherical Torus Experiment, while providing full profile capability with a moderate number of channels. The design is based on Nd:YAG lasers and avalanche photodiode detectors to allow for high repetition rate measurements. © 1999 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Review of Scientific Instruments 68 (1997), S. 2927-2964 
    ISSN: 1089-7623
    Source: AIP Digital Archive
    Topics: Physics , Electrical Engineering, Measurement and Control Technology
    Notes: Particle and energy transport in tokamaks and other toroidal confinement devices is dominated by turbulence generated by flows and gradients. In order to understand and control of this transport, diagnostic instrumentation was developed to study the structure and magnitude of microturbulent processes and to identify the origins of plasma loss. This review will cover the primary instruments that have been developed to measure fluctuating quantities associated with transport: density, δn, temperature, δT, potential, δφ, and magnetic field, δB, and their correlations. The methods discussed are Langmuir probes, heavy ion beam probes, collective and phase scintillation scattering, beam emission and ordinary spectroscopy, reflectometry and enhanced scattering, electron cyclotron emission, and several magnetic methods. The emphasis here will be on techniques applicable to microturbulence whose scale length is greater than the ion cyclotron radius and much less than the minor radius. Limitations and strengths of each method will be described and compared. Techniques will be discussed for estimating fluctuation intensities and wave number spectra or, equivalently, multipoint correlations in radial, poloidal, and toroidal directions. Large scale or magnetohydrodynamic-like plasma oscillations are typically studied with tomographic techniques or external probes and are reviewed elsewhere. © 1997 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1089-7623
    Source: AIP Digital Archive
    Topics: Physics , Electrical Engineering, Measurement and Control Technology
    Notes: Reflectometry will be used on ITER to measure the density profile in the main plasma and divertor regions, and to measure the plasma position and shape in order to provide a standby reference for the magnetic diagnostics in long pulse discharges. The high temperatures of the ITER core and the resultant significant relativistic downshift of the second-harmonic electron cyclotron absorption imply that both low-field side O-mode and high-field side lower cut-off (X−l mode) systems are required to access the full plasma profile. A low-field side upper cut-off (X−u mode) system will also be required for measurements of the scrape-off layer. For measurements of the plasma position and shape, an O-mode system is optimum due to the large range of magnetic field along the plasma periphery and the wide range of possible plasma configurations achievable on ITER. A robust real-time calibration technique of the whole transmission line is required. It is likely that an accurate estimate of the position of the plasma will require the simultaneous use of signals from the profile reflectometer. For the divertor, profiles with peak densities in the range 1019–1022/m3 are to be measured with a target resolution of 3 mm. The large density range will necessitate the use of more than one system. Installing these reflectometers on ITER incurs additional difficulties such as the routing of the millimetre wave radiation around the complicated first wall and divertor structures and design of antennas able to operate through the first wall and blanket. © 1997 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1089-7623
    Source: AIP Digital Archive
    Topics: Physics , Electrical Engineering, Measurement and Control Technology
    Notes: A large-angle, 60-GHz collective Thomson scattering (CTS) diagnostic system for localized measurements of DT alpha-particle velocity distribution and fraction is being implemented on TFTR. Calculations of expected CTS spectra, signal-to-noise ratio per receiver channel, and estimated error in determining the temperature and fraction of alpha particles are being carried out. The experimental spectra are simulated by adding noise to the theoretical calculation by a Monte Carlo technique. Error analysis is then performed by using a relative intensity calibrated nonlinear curve fitting code to calculate the desired plasma parameters (Ti, Tα, nα/ni). Simulation results indicate that expected background emission of 20 eV during Supershot in TFTR poses no problem to the experiment. Also short integration times (〈10 ms) can be used to resolve the energetic ion features, thus offering a possibility for the study of temporal evolution of energetic ion velocity distribution during a single plasma shot.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1089-7623
    Source: AIP Digital Archive
    Topics: Physics , Electrical Engineering, Measurement and Control Technology
    Notes: Thomson scattering systems capable of providing snapshot profiles of electron temperature and density with high spatial resolution (〉50 points) have become routine diagnostics on the Princeton large torus (PLT), Princeton divertor experiment (PDX), and tokamak fusion test reactor (TFTR) tokamaks. The design parameters of these systems are compared. Particular attention is given to describing those new components and techniques which have contributed most to improved data quality and reliability in the ten-year evolution of these systems. Examples of recent TFTR Te(R) and ne(R) profiles are presented.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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