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  • 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 Quaternary Science Reviews 76 (2013): 16-28, doi:10.1016/j.quascirev.2013.05.024.
    Description: A proxy system model may be defined as the complete set of forward and mechanistic processes by which the response of a sensor to environmental forcing is recorded and subsequently observed in a material archive. Proxy system modeling complements and sharpens signal interpretations based solely on statistical analyses and transformations; provides the basis for observing network optimization, hypothesis testing, and data-model comparisons for uncertainty estimation; and may be incorporated as weak but mechanistically-plausible constraints into paleoclimatic reconstruction algorithms. Following a review illustrating these applications, we recommend future research pathways, including development of intermediate proxy system models for important sensors, archives, and observations; linking proxy system models to climate system models; hypothesis development and evaluation; more realistic multi-archive, multi-observation network design; examination of proxy system behavior under extreme conditions; and generalized modeling of the total uncertainty in paleoclimate reconstructions derived from paleo-observations.
    Description: MNE and DMT were funded by NOAA/C2D2 grant NA10OAR4310115; SETW gratefully acknowledges support from an American Association of UniversityWomen Dissertation Fellowship. Work cited in this review was supported by NSF grants 0349356, 0724802 and 0902715, NOAA grants NA06OAR4310115 and NA08OAR4310682, and the University of Arizona’s Department of Geosciences and Institute of the Environment.
    Keywords: Forward modeling ; Observational network optimization ; Data-model comparison ; Hypothesis evaluation ; Reconstruction ; Uncertainty modeling
    Repository Name: Woods Hole Open Access Server
    Type: Article
    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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