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  • Copernicus Publications on behalf of the European Geosciences Union  (1)
  • The American Association for Cancer Research (AACR)  (1)
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Years
  • 1
    Publication Date: 2022-05-25
    Description: © The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Climate of the Past 9 (2013): 1481-1493, doi:10.5194/cp-9-1481-2013.
    Description: We present a Bayesian model for estimating the parameters of the VS-Lite forward model of tree-ring width for a particular chronology and its local climatology. The scheme also provides information about the uncertainty of the parameter estimates, as well as the model error in representing the observed proxy time series. By inferring VS-Lite's parameters independently for synthetically generated ring-width series at several hundred sites across the United States, we show that the algorithm is skillful. We also infer optimal parameter values for modeling observed ring-width data at the same network of sites. The estimated parameter values covary in physical space, and their locations in multidimensional parameter space provide insight into the dominant climatic controls on modeled tree-ring growth at each site as well as the stability of those controls. The estimation procedure is useful for forward and inverse modeling studies using VS-Lite to quantify the full range of model uncertainty stemming from its parameterization.
    Description: This work was supported in part by an American Association of University Women Dissertation Fellowship and grants NSF ATM-0724802, NSF ATM-0902715, NSF DMS- 1204892, and NOAA NA060OAR4310115.
    Repository Name: Woods Hole Open Access Server
    Type: Article
    Format: application/zip
    Format: application/pdf
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  • 2
    Publication Date: 2018-04-03
    Description: Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked EGFR (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intravital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular cross-talk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited.Significance: Signaling by the MNK kinase is essential in inflammatory breast cancer, and it can be targeted to inhibit XIAP–NFκB signaling and the aggressive phenotype of this malignancy. Cancer Res; 78(7); 1726–38. ©2018 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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