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  • Wiley-Blackwell  (14)
  • Nature Publishing Group (NPG)  (7)
  • American Society of Hematology (ASH)  (3)
Document type
  • 11
    Publication Date: 2012-08-10
    Description: Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.
    Keywords: Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 12
    Publication Date: 2018-12-07
    Description: The CD33-targeting bispecific T-cell engager (BiTE) AMG 330 proved to be highly efficient in mediating cytolysis of acute myeloid leukemia (AML) cells in vitro and in mouse models. Yet, T-cell activation is correlated with upregulation of programmed cell death-ligand 1 (PD-L1) and other inhibitory checkpoints on AML cells that confer adaptive immune resistance. PD-1 and PD-L1 blocking agents may counteract T-cell dysfunction, however, at the expense of broadly distributed immune-related adverse events (irAEs). We developed a bifunctional checkpoint inhibitory T cell–engaging (CiTE) antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade. This is accomplished by fusing the extracellular domain of PD-1 (PD-1 ex ), which naturally holds a low affinity to PD-L1, to an αCD3.αCD33 BiTE-like scaffold. By a synergistic effect of checkpoint blockade and avidity-dependent binding, the PD-1 ex attachment increases T-cell activation (3.3-fold elevation of interferon-) and leads to efficient and highly selective cytotoxicity against CD33 + PD-L1 + cell lines (50% effective concentration = 2.3-26.9 pM) as well as patient-derived AML cells (n = 8). In a murine xenograft model, the CiTE induces complete AML eradication without initial signs of irAEs as measured by body weight loss. We conclude that our molecule preferentially targets AML cells, whereas high-affinity blockers, such as clinically approved anticancer agents, also address PD-L1 + non-AML cells. By combining the high efficacy of T-cell engagers with immune checkpoint blockade in a single molecule, we expect to minimize irAEs associated with the systemic application of immune checkpoint inhibitors and suggest high therapeutic potential, particularly for patients with relapsed/ refractory AML.
    Keywords: Immunobiology and Immunotherapy, Myeloid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 13
    Publication Date: 2018-10-24
    Description: De novo gene mutations in normal human memory B cells De novo gene mutations in normal human memory B cells, Published online: 23 October 2018; doi:10.1038/s41375-018-0289-4 De novo gene mutations in normal human memory B cells
    Print ISSN: 0887-6924
    Electronic ISSN: 1476-5551
    Topics: Medicine
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  • 14
    Publication Date: 2013-11-08
    Description: De-targeting by miR-143 decreases unwanted transgene expression in non-tumorigenic cells Gene Therapy 20, 1104 (November 2013). doi:10.1038/gt.2013.37 Authors: F Kopp, M Schnoedt, R Haase, E Wagner, A Roidl & M Ogris
    Keywords: cancernonviralmicroRNA-143binding sitesde-targeting
    Print ISSN: 0969-7128
    Electronic ISSN: 1476-5462
    Topics: Biology , Medicine
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  • 15
    Publication Date: 2013-11-30
    Description: Variability in floral, fruit, and seed characteristics, and oil content of 15 accession of Jatropha curcas during early development were assessed during two flowering periods in south Florida subtropical climate. The two flowering periods had leaf flushing in March. Field evaluation using 18 quantitative traits showed significant variation among accessions. The number of female flowers and female : male flower ratio ranged from 1 to 15 and 1 : 8.8 to 1 : 67.8, respectively. Fruit set by natural pollination was 89 and 66% during the first (1st) and second (2nd) flowering periods, respectively. A higher number of female-type inflorescences were observed during summer. There were significant differences in seed traits, except for number of seeds per fruit. Accession TREC 31 had the highest individual seed dry weight and 100-seed weight (0.83 g and 79.7 g, respectively). The oil content varied from 19.30% to 35.62%. Seed dry weight had positive correlation with seed fresh weight, seed length, seed thickness, seed width, and 100-seed weight, but negative correlation with oil content. Based on the cluster analysis using 15 morphological traits, jatropha accessions were grouped into five main clusters and accessions from different geographic regions grouped together in a cluster. Principal component analyses (PCA) revealed morphological variation. The first three components explained 73.5% of the total variation and seed dry weight, 100-seed weight, total flowers per inflorescence, male flowers per inflorescence and fruit set can be used to distinguish accessions. The PCA also indicated that flowering traits were more influenced by seed origin while seed traits were affected by flowering spans. Although evaluations were performed in plants during the juvenile phase, accessions TREC 31 and TREC 55 had superior averages for almost all characters evaluated. These results provide a preliminary assessment of the high variability in jatropha accessions evaluated and their potential for use in breeding and genetic improvement programs.
    Print ISSN: 1757-1693
    Electronic ISSN: 1757-1707
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by Wiley-Blackwell
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  • 16
    Publication Date: 2014-04-24
    Description: Titan, Saturn's largest satellite, is subject to solid body tides exerted by Saturn on the time-scale of its orbital period. The tide-induced internal redistribution of mass results in tidal stress variations, which could play a major role for Titan's geologic surface record. We construct models of Titan's interior that are consistent with the satellite's mean density, polar moment-of-inertia factor, obliquity, and tidal potential Love number k 2 as derived from Cassini observations of Titan's low-degree gravity field and rotational state. In the presence of a global liquid reservoir, the tidal gravity field is found to be consistent with a subsurface water-ammonia ocean more than 180 km thick and overlain by an outer ice shell of less than 110 km thickness. The model calculations suggest comparatively low ocean ammonia contents of less than 5 wt.-% and ocean temperatures in excess of 255 K, i.e., higher than previously thought, thereby substantially increasing Titan's potential for habitable locations. The calculated diurnal tidal stresses at Titan's surface amount to 20 kPa, almost comparable to those expected at Enceladus and Europa. Tidal shear stresses are concentrated in the polar areas, while tensile stresses predominate in the near-equatorial, mid-latitude areas of the sub- and anti-saturnian hemispheres. The characteristic pattern of maximum diurnal tidal stresses is largely compliant with the distribution of active regions such as cryovolcanic candidate areas. The latter could be important for Titan's habitability since those may provide possible pathways for liquid water-ammonia outbursts on the surface and the release of methane in the satellite's atmosphere.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
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  • 17
    Publication Date: 2016-05-06
    Description: Nature Nanotechnology 11, 432 (2016). doi:10.1038/nnano.2015.339 Authors: K. Wagner, A. Kákay, K. Schultheiss, A. Henschke, T. Sebastian & H. Schultheiss In the research field of magnonics, it is envisaged that spin waves will be used as information carriers, promoting operation based on their wave properties. However, the field still faces major challenges. To become fully competitive, novel schemes for energy-efficient control of spin-wave propagation in two dimensions have to be realized on much smaller length scales than used before. In this Letter, we address these challenges with the experimental realization of a novel approach to guide spin waves in reconfigurable, nano-sized magnonic waveguides. For this purpose, we make use of two inherent characteristics of magnetism: the non-volatility of magnetic remanence states and the nanometre dimensions of domain walls formed within these magnetic configurations. We present the experimental observation and micromagnetic simulations of spin-wave propagation inside nano-sized domain walls and realize a first step towards a reconfigurable domain-wall-based magnonic nanocircuitry.
    Print ISSN: 1748-3387
    Electronic ISSN: 1748-3395
    Topics: Physics
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  • 18
    Publication Date: 2016-08-23
    Description: ABSTRACT Between the years 2008 and 2013, approximately 67 kilotons of CO 2 have been injected at the Ketzin site, Germany. As part of the geophysical monitoring programme, time-lapse electrical resistivity tomography has been applied using crosshole and surface-downhole measurements of electrical resistivity tomography. The data collection of electrical resistivity tomography is partly based on electrodes that are permanently installed in three wells at the site (one injection well and two observation wells). Both types of ERT measurements consistently show the build-up of a CO 2 -related resistivity signature near the injection point. Based on the imaged resistivity changes and a petrophysical model, CO 2 saturation levels are estimated. These CO 2 saturations are interpreted in conjunction with CO 2 saturations inferred from neutron-gamma loggings. Apart from the CO 2 –brine substitution response in the observed resistivity changes, significant imprints from the dynamic behaviour of the CO 2 in the reservoir are observed.
    Print ISSN: 0016-8025
    Electronic ISSN: 1365-2478
    Topics: Geosciences , Physics
    Published by Wiley-Blackwell
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  • 19
    Publication Date: 2013-03-10
    Description: Jatropha curcas L. (jatropha) is a species identified for biofuel production because of the high quality of the oil produced by its seeds. However, jatropha is undomesticated and little information is available about its reproductive characteristics. Breeding and genetic improvement programs are much needed for the jatropha development as a bioenergy crop. Information about floral display and mode of reproduction are considered essential for breeding programs. In this study, the total number of female flowers, male to female flower ratio, fruit set, in vitro pollen germination, and the formation of fruits by apomixis, self-pollination, and natural pollination were evaluated in 17 jatropha accessions planted in South Florida. The total number of female flowers per inflorescence and male to female flower ration ranged from 2.8 to 9.1 and 9.9:1 to 55.4 : 1, respectively. During summer 2011, high fruit setting average was observed (75.5%). In vitro pollen germination varied from 64.6% during spring 2011 to 51.6% during fall 2011. The fruit set observed was from 10.1% to 64.0% through natural pollination and apomixes, respectively. Characteristics such as fruit fresh weight, number of seeds per fruit, seed dry weight, and oil content were influenced by mode of reproduction.
    Print ISSN: 1757-1693
    Electronic ISSN: 1757-1707
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by Wiley-Blackwell
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  • 20
    Publication Date: 2014-03-11
    Description: Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia Cell Death and Differentiation 21, 655 (April 2014). doi:10.1038/cdd.2013.198 Authors: J Luther, K Ubieta, N Hannemann, M Jimenez, M Garcia, C Zech, G Schett, E F Wagner & A Bozec
    Keywords: AP-1/Fra-2HIFsadipocyteapoptosis
    Print ISSN: 1350-9047
    Electronic ISSN: 1476-5403
    Topics: Biology , Medicine
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