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  • 1
    In: Alzheimer's & Dementia, Wiley, Vol. 6, No. 4S_Part_18 ( 2010-07)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 2201940-6
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2562-2562
    Abstract: Patient stratification based on target protein expressions or mutations alone has limitations in selecting efficacious therapeutic regimens for solid tumors. Information on the activation status of signaling pathway proteins as determined by their phosphorylation states and the level of expression, profiling of growth factors responsible for its activation, and their dimerization partners, can significantly influence clinical decisions. Herein we report a comprehensive analysis of key receptor tyrosine kinases (HER1, HER2, p95HER2, HER3, cMET, IGF1R, FGFRs, and others) and their downstream signal proteins (PI3K, Shc, AKT, MEK, ERK, PRAS40, RPS6, P70S6K, RSK), and dimerization partners (HER1:HER2, HER2:HER3, HER1:HER3, and others), and secreted growth factors (AREG, EREG, NRG1, HB-EGF, HGF, BTC, EGF, TGF, VEGF, and IGF-1) based on a multiplexed immunoarray CEER (Collaborative Enzyme Enhanced Reactive-immunoassay) platform. CEER platform utilizes the formation of an unique “triple-antibody-enzyme-channeling” immuno-complex. This complex requires co-localization of two detector-antibodies conjugated with corresponding channeling-enzymes once target proteins are bound by the capture antibodies. The immuno-collaboration between two detector enzymes, glucose oxidase (GO, conjugated to anti-target protein antibodies) and horseradish peroxidase (HRP, conjugated to anti-phosphorylated sites within the target) via target-specific, tyramide-mediated signal amplification enables target protein expression /phosphorylation profiling with validated analytical sensitivity between 1 to 10 cells. Using the CEER platform, quantitative modulations of target protein(s) in response to targeted agent(s) and treatment effect on associated downstream and upstream pathway proteins were measured. Due to the extreme sensitivity and specificity, CEER can be utilized in clinical samples with limited availability (e.g., FNA or CTCs). A comprehensive signaling pathway analysis can be a critical guide for selecting effective clinical strategies for targeted drug combinations or sequential therapeutic regimens. In addition, continued signaling pathway profiling after drug administration can monitor drug response and provide valuable information on potential drug resistance mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2562. doi:1538-7445.AM2012-2562
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5632-5632
    Abstract: In wide range of human cancer, the phosphoinositide 3-kinase (PI3K)/AKT and RAF/MEK/ERK signaling pathways are activated, regulating cell growth, metabolism, survival, and proliferation. Inhibition of either PI3K/AKT or MEK/ERK signaling pathway as a single-agent targeted therapy is often ineffective due to feedback mechanisms in which inhibition of one signaling pathway leads to activation of another. Treatment with a single-agent MEK inhibitor substantially increases ERBB3/PI3K/AKT phospho levels by relieving an ERK mediated negative feedback on threonine phosphorylation on the juxtamembrane domains of EGFR (T669) and HER2 (T677). Loss of inhibitory threonine phosphorylation in EGFR and HER2 suggests that increase in phospho HER3 levels may be due to formation of heterodimers (EGFR:HER3 and HER2:HER3) driving trans-phosphorylation of ERBB3. Herein we report, utilizing Collaborative Enzyme Enhanced Reactive (CEERTM) immunoassay, comprehensive analysis of key receptor tyrosine kinases (HER1, HER2, HER3, cMET, IGF1R, and others) and their downstream signal proteins (PI3K, Shc, AKT, MEK, ERK, PRAS40, RPS6, P70S6K, RSK), and dimerization partners (HER1:HER2, HER2:HER3, HER1:HER3, and HER3:PI3K) in MDA-MB-468, and BT474 treated with either MEK inhibitor alone (AZD6244) or in combination with PI3K inhibitor (GDC0941). CEER platform utilizes the formation of an unique “triple-antibody-enzyme-channeling” immuno-complex, requiring minimal sample amount. At MEK inhibitor concentration of 1μmol/L, both MDA-MB-468 and BT474 cells sufficiently inhibited ERK and RSK phosphorylation. In each cell line, we observed increase in phospho-HER3 and activated HER3:PI3K complex, a phospho-tyrosine signaling cascades that directly activate AKT. Levels of HER1:3 and HER2:3 dimers were elevated in MDA-MB-468 and BT474, respectively post MEK inhibitor treatment. Feedback activation of AKT with AZD6244 was suppressed when combined with GDC0941 at concentration of 1μmol/L. With combination of MEK and PI3K inhibitors, levels of HER1:3 and HER2:3 dimers were unaffected in their respective cell line, but HER3:PI3K complex was completely suppressed in both cell lines. The data suggests that loss of negative feedback with MEK inhibition alone promoted alternate oncogenic AKT signaling. As often the case, single-targeted therapies are ineffective, since the pathway it is targeted to inhibit, leads to feedback contributing to therapeutic resistance. Utilizing CEERTM, clinical specimens with limited availability can be profiled in a comprehensive manner for potential feedback mechanisms and selection of combinational therapies suppressing both the oncoprotein and the feedback program. Citation Format: Nicholas Hoe, Michael Mateling, Yating Ma, Kelly Jin, JinYao Zhou, Richard Kirkland, Crystal Kuy, Xinjun Liu, Phillip Kim, Sharat Singh. MEK inhibition leads to elevated HER3:PI3K in EGFR or HER2 driven cancer through feedback induction of HER1:3 and HER2:3 dimers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5632. doi:10.1158/1538-7445.AM2013-5632
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 39 ( 2013-09-25), p. 15596-15602
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 39 ( 2013-09-25), p. 15596-15602
    Abstract: Brain-derived neurotrophic factor (BDNF) improves molecular, cellular, and behavioral measures of neural dysfunction in genetic models of Alzheimer's disease (Blurton-Jones et al., 2009; Nagahara et al., 2009). However, BDNF treatment after disease onset has not been reported to improve neuronal survival in these models. We now report prevention of neuronal loss with early life BDNF treatment in mutant mice expressing two amyloid precursor protein (APP) mutations associated with early-onset familial Alzheimer's disease. APP transgenic mice underwent lentiviral BDNF gene delivery into the entorhinal cortices at age 2 months and were examined 5 months later. BDNF-treated mice exhibited significant improvements in hippocampal-dependent contextual fear conditioning compared with control-treated APP mice ( p 〈 0.05). Stereological analysis of entorhinal cortical cell number demonstrated ∼20% reductions in neuronal number in layers II-VI of the entorhinal cortex in untreated APP mutant mice compared with wild-type mice ( p 〈 0.0001), and significant amelioration of cell loss by BDNF ( p 〈 0.001). Moreover, BDNF gene delivery improved synaptophysin immunoreactivity in the entorhinal cortex and, through anterograde BDNF transport, in the hippocampus ( p 〈 0.01). Notably, BDNF did not affect amyloid plaque numbers, indicating that direct amyloid reduction is not necessary to achieve significant neuroprotective benefits in mutant amyloid models of Alzheimer's disease.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 5
    In: Bulletin of the American Meteorological Society, American Meteorological Society, Vol. 102, No. 7 ( 2021-07), p. E1317-E1339
    Abstract: A multisensor snowfall observational suite has been deployed at the Marquette, Michigan, National Weather Service Weather Forecast Office (KMQT) since 2014. Micro Rain Radar (MRR; profiling radar), Precipitation Imaging Package (PIP; snow particle imager), and ancillary ground-based meteorological observations illustrate the unique capabilities of these combined instruments to document radar and concomitant microphysical properties associated with northern Great Lakes snowfall regimes. Lake-effect, lake-orographic, and transition event case studies are presented that illustrate the variety of snowfall events that occur at KMQT. Case studies and multiyear analyses reveal the ubiquity of snowfall produced by shallow events. These shallow snowfall features and their distinctive microphysical fingerprints are often difficult to discern with conventional remote sensing instruments, thus highlighting the scientific and potential operational value of MRR and PIP observations. The importance of near-surface lake-orographic snowfall enhancement processes in extreme snowfall events and regime-dependent snow particle microphysical variability controlled by regime and environmental factors are also highlighted.
    Type of Medium: Online Resource
    ISSN: 0003-0007 , 1520-0477
    Language: Unknown
    Publisher: American Meteorological Society
    Publication Date: 2021
    detail.hit.zdb_id: 2029396-3
    detail.hit.zdb_id: 419957-1
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  • 6
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4273-4273
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4273-4273
    Abstract: Fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) are currently under investigation as therapeutic targets for the treatment of breast cancer. FGFR1 amplifications range from 7.5-17% in breast cancers and are associated with a shorter overall survival. FGFR1 amplified cell lines drive activation of AKT and ERK pathways and are highly sensitive to FGFR1 inhibition, suggesting an oncogenic addiction to FGFR1. FGFR2 has been reported to be activated in lapatinib-resistant, HER2-positive cells. Likewise, FGFR3 expression levels are often elevated in tamoxifen-resistant, ER positive patients. FGFR 4 overexpression correlated with poor response to chemotherapy due to activation of MAPK and increase in B-cell lymphoma extra large (BCL-XL) levels. Using a highly sensitive, novel proximity mediated immuno-microarray, Collaborative Enzyme Enhanced Reactive-immunoassay (CEERTM), this study seeks to determine whether FGFR signal transduction pathway inhibition modulate ErbB receptor tyrosine kinases and AKT/ERK signal transduction pathway in cell lines expressing varying levels of FGFR and ErbB receptors. FGFR 1, 2, 3, and 4 amplified cell lines (MDA-MB-134VI (KRAS), SNU16, RT112, and MDA-MB-453) were individually treated with varying dosages (1, 10, 100, and 1000nM) of pan FGFR inhibitors (AZD4547 and Ponatinib-AP24534) in presence of corresponding FGF ligand (FGF1, FGF7, FGF9, and FGF19). Expression and activation of FGFR 1, 2, 3, 4 and EGFR, HER2, HER3, HER4 and downstream signaling proteins FRS2, AKT, ERK, MEK, and RSK were measured utilizing CEERTM. Both FGFR inhibitors sufficiently inhibited phosphorylation of FGFRs in each of the four FGFR amplified cell line. In MDA-MB-453, FGFR4 inhibition increased phosphorylation of HER2, and HER3 along with AKT. In MDA-MB-134, FGFR1 inhibition decreased levels of HER3 phosphorylation along with reduction in phosphorylated ERK, MEK, and RSK. In SNU16, FGFR2 inhibition led to a decrease in EGFR, HER2, and HER3 phosphorylation along with reduction in phosphorylated MEK, ERK, and RSK. Analysis of RT112 and additional cell lines with varying levels of ErbB and FGFR receptor tyrosine kinases are currently in progress. Our data suggests that FGFR inhibition may modulate parallel / compensatory ErbB and other signaling pathway as observed in this study. Utilizing CEERTM, comprehensive profiling may provide unique insight into potential feedback mechanisms in each patient and evidence for rational selection of appropriate combinational therapies. Citation Format: Nicholas Hoe, Kelly Jin, Yating Ma, Crystal Kuy, Michael Mateling, JinYao Zhou, Richard Kirkland, Saswati Hazara, Phillip Kim, Xinjun Liu, Sharat Singh. FGFR inhibition modulates ErbB receptor tyrosine phosphorylation in FGFR amplified cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2013-4273
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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