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  • 1
    Publication Date: 2018-01-03
    Description: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2 + metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2 + tumors, are not well understood. We used HER2 + cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1–resistant population was generated. T-DM1–resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non–cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells. Intriguingly, T-ADCs using auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors that remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1)–positive puncta and alter their trafficking to the lysosome compared with N87 cells. T-DM1 colocalization into intracellular CAV1-positive puncta correlated with reduced response to T-DM1 in a panel of HER2 + cell lines. Together, these data suggest that caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1. Mol Cancer Ther; 17(1); 243–53. ©2017 AACR .
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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  • 2
    Publication Date: 2018-03-06
    Description: Purpose: We hypothesized that axitinib is active with an improved safety profile in nasopharyngeal carcinoma (NPC). Experimental Design: We evaluated axitinib in preclinical models of NPC and studied its efficacy in a phase II clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice daily in continuous 4-week cycles. Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria for more than 3 months. Results: We recruited 40 patients, who received a median of 3 lines of prior chemotherapy. Axitinib was administered for a mean of 5.6 cycles, with 16 patients (40%) receiving ≥6 cycles. Of 37 patients evaluable for response, CBR was 78.4% (95% CI, 65.6%–91.2%) at 3 months and 43.2% (30.4%–56.1%) at 6 months. Grade 3/4 toxicities were uncommon, including hypertension (8%), diarrhea (5%), weight loss (5%), and pain (5%). All hemorrhagic events were grade 1 (15%) or grade 2 (3%). Elevated diastolic blood pressure during the first 3 months of axitinib treatment was significantly associated with improved overall survival (HR, 0.29; 95% CI, 0.13–0.64, P = 0.0012). Patient-reported fatigue symptom was associated with hypothyroidism ( P = 0.039). Axitinib PK parameters (C max and AUC (0-t) ) were significantly correlated with tumor response, toxicity, and serum thyroid-stimulating hormone changes. Conclusions: Axitinib achieved durable disease control with a favorable safety profile in heavily pretreated NPC patients. Clin Cancer Res; 24(5); 1030–7. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Smooth, c-axis oriented, superconducting thin films of YBa2Cu3O7−x and DyBa2Cu3O7−x have been grown on (100) MgO by organometallic molecular-beam epitaxy. To our knowledge this is the first report of this technique for the fabrication of this class of high Tc superconductors. Y (or Dy) β-diketonate organometallic sources are utilized with Ba and Cu metallic sources. Films are grown in situ by codepositing from these sources in an ozone ambient with a substrate temperature of 700 °C. The use of an active oxygen source (ozone) is required for decomposition of the organometallic sources as well as for the attainment of superconducting films in situ. The films are characterized by Tc's as high as 85 K and Jc's of 1.2×106 A/cm2 at 12 K and 2.4×103 A/cm2 at 77 K. In addition to the four point Tc and Jc results, alternating-current susceptibility measurements are also reported. The composition of the films has been determined by Rutherford backscattering spectroscopy, Auger and secondary ion mass spectroscopy analysis, with the smoothness of the films characterized by scanning tunneling microscopy.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Physics of Fluids 30 (1987), S. 2054-2062 
    ISSN: 1089-7666
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Some studies of forced and unforced plane turbulent mixing layers have been conducted using two experimental and two computational approaches. The present paper contains an overall comparison and discussion of the measured and computed results. The experimental results include flow-visualization data using the smoke-laser technique and mean flow and turbulence measurements obtained with hot X wires and a two-component laser-Doppler velocimeter (LDV). The mean flow and turbulence results indicate that the two experimental techniques agree reasonably well for this shear flow. Two-dimensional computations of the measured mixing layers have also been conducted in a coordinated effort; one method uses the inviscid discrete vortex technique for a spatially developing layer and the other is based on an approximation to the Reynolds-averaged Navier–Stokes equations. The vortex method was found to give excellent results for the forced mixing layer while the Reynolds-averaged computations, with a modified turbulence model, were particularly successful at capturing the near-field viscous behavior that included the splitter plate wake.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    [S.l.] : American Institute of Physics (AIP)
    Journal of Applied Physics 70 (1991), S. 3251-3255 
    ISSN: 1089-7550
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The isothermal decay of the second-order nonlinear optical susceptibility of a guest-host azo dye methacrylate film was measured by second-harmonic generation at a series of temperatures. The decay curves were fit to Williams–Watt–Kohlrausch stretched exponentials. The activation energies and pre-exponential factors were found to agree with those derived from nonisothermal electric-field-induced second-harmonic generation measurements on similar films. It is concluded that a common underlying process involving a distribution of local relaxations governs the film behavior.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 63 (1993), S. 1005-1007 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Epitaxial barriers of ferromagnetic SrRuO3 have been used to fabricate high Tc superconductor-normal-superconductor Josephson junctions in the edge junction geometry. At small barrier thicknesses the SrRuO3 junctions follow the behavior of nonferromagnetic but otherwise closely related CaRuO3 junctions. A rapid disappearance of critical current is observed when the barrier thickness is increased to 250 A(ring). Possible origins of such a large critical thickness are discussed.
    Type of Medium: Electronic Resource
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