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  • 1
    Publication Date: 2019-11-13
    Description: AMG 701 is a half-life extended BiTE® (bispecific T-cell engager) targeting the B cell maturation antigen (BCMA). Here, we confirmed AMG 701-mediated T cell-redirected lysis of MM cells, defined immunomodulatory effects of AMG 701, and investigated combination potential of AMG 701 with immunomodulatory drugs (IMiDs) in human MM. Firstly, AMG 701 induced specific and efficacious T cell-dependent cytotoxicity (TDCC) against all MM cell lines tested, regardless of sensitivity to current anti-MM agents and expression levels of BCMA. AMG 701-induced TDCC was minimally affected in the presence of myeloma-supporting cells and cytokines in the bone marrow (BM) microenvironment, including osteoclasts (OCs), BM stromal cells (BMSCs), and a proliferation-inducing ligand (100 ng/ml). Importantly, AMG 701 induced lysis of autologous patient cells from the relapse and refractory stage of MM (RRMM). AMG 701 rapidly upregulated cell surface expression of CD107a and the production of IFNγ and TNFα, more so in CD8 than CD4 T subsets. It stimulated the proliferation and activation of T cells, to a greater extent in CD8 vs CD4 T cells, leading to significantly increased ratios of CD8/CD4 T cells. Significantly, AMG 701 induced differentiation of naive T cells (CD4 and CD8) to T cells with memory phenotype. This includes central memory (CM), effector memory (EM) T cells, and stem cell like memory cells. Time-course immunophenotyping studies showed that AMG 701 transiently upregulated the expression of key immune checkpoint and costimulatory markers on both CD4 and CD8 T cells. The induced T cells purified from ex vivo co-cultures still effectively lysed MM cells with lower BCMA levels. This may suggest an increased T cell clonality. Furthermore, IMiDs (len or pom) enhanced AMG 701-mediated TDCC against MM cells at earlier time points, lower E/T ratios, lower concentrations, or in the presence of immunosuppressive OCs or BMSCs. The combination AMG 701 and IMiDs maximized MM cell lysis accompanied with a decreased EC50 value. Combined treatments induce a more pronounced immunomodulation than AMG 701 alone in the presence of OCs, as evidenced by higher percentage of CM+EM and CD8/CD4 ratio at d8. AMG 701 with IMiDs combination significantly enhance AMG 701-mediated autologous patient MM cell lysis in a synergistic manner (combination index 〈 1). In the human NCI-H929 xenograft model reconstituted with human T effector cells, AMG 701 effectively blocked tumor growth 5d after the first injection, regardless of doses (0.02-2 mg/kg). Tumors were completely eradicated following 3 separate injections in the host without weight loss. Next, sub-optimal doses and treatment schedules for AMG 701 and len were then used to investigate in vivo anti-MM effects by the combination vs monotherapy. Mice receiving MM cells were treated, from d15 until the end of the study, with len once daily, AMG 701 once weekly, or combination of AMG 701 and len. Two days after the first drug administration, all three treatments significantly inhibited MM tumor growth in mice (p
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2017-04-12
    Description: Quasi-decadal variability in solar irradiance has been suggested to exert a substantial effect on Earth’s regional climate. In the North Atlantic sector, the 11-year solar signal has been proposed to project onto a pattern resembling the North Atlantic Oscillation (NAO), with a lag of a few years due to ocean-atmosphere interactions. The solar/NAO relationship is, however, highly misrepresented in climate model simulations with realistic observed forcings. In addition, its detection is particularly complicated since NAO quasi-decadal fluctuations can be intrinsically generated by the coupled ocean-atmosphere system. Here we compare two multi-decadal ocean-atmosphere chemistry-climate simulations with and without solar forcing variability. While the experiment including solar variability simulates a 1–2-year lagged solar/NAO relationship, comparison of both experiments suggests that the 11-year solar cycle synchronizes quasi-decadal NAO variability intrinsic to the model. The synchronization is consistent with the downward propagation of the solar signal from the stratosphere to the surface.
    Type: Article , PeerReviewed
    Format: text
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  • 3
    Publication Date: 2019-09-23
    Description: Large changes in solar ultraviolet radiation can indirectly affect climate1 by inducing atmospheric changes. Specifically, it has been suggested that centennial-scale climate variability during the Holocene epoch was controlled by the Sun2, 3. However, the amplitude of solar forcing is small when compared with the climatic effects and, without reliable data sets, it is unclear which feedback mechanisms could have amplified the forcing. Here we analyse annually laminated sediments of Lake Meerfelder Maar, Germany, to derive variations in wind strength and the rate of 10Be accumulation, a proxy for solar activity, from 3,300 to 2,000 years before present. We find a sharp increase in windiness and cosmogenic 10Be deposition 2,759  ±  39 varve years before present and a reduction in both entities 199  ±  9 annual layers later. We infer that the atmospheric circulation reacted abruptly and in phase with the solar minimum. A shift in atmospheric circulation in response to changes in solar activity is broadly consistent with atmospheric circulation patterns in long-term climate model simulations, and in reanalysis data that assimilate observations from recent solar minima into a climate model. We conclude that changes in atmospheric circulation amplified the solar signal and caused abrupt climate change about 2,800 years ago, coincident with a grand solar minimum.
    Type: Article , PeerReviewed
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  • 4
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    Nature Publishing Group
    In:  Nature Geoscience, 4 (11). pp. 735-736.
    Publication Date: 2012-08-02
    Description: The impact of solar activity on climate has been debated heatedly. Simulations with a climate model using new observations of solar variability suggest a substantial influence of the Sun on the winter climate in the Northern Hemisphere.
    Type: Article , PeerReviewed
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  • 5
    Publication Date: 2019-09-23
    Description: Changes in solar activity have previously been proposed to cause decadal- to millennial-scale fluctuations in both the modern and Holocene climates1. Direct observational records of solar activity, such as sunspot numbers, exist for only the past few hundred years, so solar variability for earlier periods is typically reconstructed from measurements of cosmogenic radionuclides such as 10Be and 14C from ice cores and tree rings2, 3. Here we present a high-resolution 10Be record from the ice core collected from central Greenland by the Greenland Ice Core Project (GRIP). The record spans from 22,500 to 10,000 years ago, and is based on new and compiled data4, 5, 6. Using 14C records7, 8 to control for climate-related influences on 10Be deposition, we reconstruct centennial changes in solar activity. We find that during the Last Glacial Maximum, solar minima correlate with more negative δ18O values of ice and are accompanied by increased snow accumulation and sea-salt input over central Greenland. We suggest that solar minima could have induced changes in the stratosphere that favour the development of high-pressure blocking systems located to the south of Greenland, as has been found in observations and model simulations for recent climate9, 10. We conclude that the mechanism behind solar forcing of regional climate change may have been similar under both modern and Last Glacial Maximum climate conditions.
    Type: Article , PeerReviewed
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