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  • 1
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    The @journal of physical chemistry 〈Washington, DC〉 89 (1985), S. 5459-5464 
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Earth and Planetary Science Letters 81 (1986), S. 7-14 
    ISSN: 0012-821X
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Geosciences , Physics
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 152 (1992), S. 458-466 
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: We evaluated the role of cytoskeletal elements in the degradation of endogenous proteins via autophgy using biochemical and morphological techniques. In the absence of exogenous amino acids, degradation of endogenous proteins was enhanced in cultured normal rat kidney cells. This enhanced degradative state was accompanied by a 4-fold increase in the occurrence of autophagic vacuoles. In the presence of drugs that induce the depolymerization of microfilaments (cytochalasins B and D) or microtubules (nocodazole), protein degradation was not enhanced in nutrient-deprived cells. Although these drugs had similar inhibitory effects on the protein degradation, their effect on autophagy differed. Cytochalasins B and D interfered with the formation of the autophagosome. In cells treated with these drugs, the fractional volume represented by autophagic vaculoes was not substantially increased despite nutrient depletion. On the contrary, nocodazole appeared to have no effect on the formation of autophagosomes. Instead, this drug suppressed the delivery of hydrolytic enzymes, thereby resulting in an accumulation of acidic autophagic vacuoles containing undegraded cellular components. © 1992 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2013-07-04
    Description: A bstract :  Evaluating the timing and origin of quartz cement is central to understanding how porosity is lost in sandstones during burial. Kinetic models of quartz cementation have been calibrated using large–scale datasets but have never been tested at the microscopic level at which cement forms. Here, we use high-precision, in situ oxygen isotope analyses on sandstone from the Jurassic Ness Formation from the North Sea to reveal the growth history of single quartz overgrowths to a resolution of 2 µm. Measured 18 O (cement) range from +28 to +20 V-SMOW in early to late cement and are consistent with quartz cementation models that propose the bulk of quartz precipitates as a continuous process beginning at 60–70 °C. Quantitative X-ray Diffraction analyses and clay mineralogical analysis of interbedded shales are inconsistent with a silica source from shale, implying that silica for the cement is sourced internally to the sand. These isotope data are broadly consistent with predictive, conceptual quartz cementation models and provide a critical link from micron-scale measurements to basin-scale predictions and observations.
    Print ISSN: 1527-1404
    Topics: Geosciences
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  • 5
    Publication Date: 2014-12-27
    Description: Skin cancer is the most common cancer in the United States and is mainly caused by environmental UV radiation. Reducing skin cancer incidence is becoming an urgent issue. The stress-inducible protein Sestrin2 (Sesn2) plays an important role in maintaining redox and metabolic homeostasis and their related pathologies. However, the role of Sesn2 in cancer remains unclear. Here we show that UVB radiation induces Sesn2 expression in normal human keratinocytes, mouse skin, normal human melanocytes, and melanoma cells. In addition, Sesn2 promotes AKT activation through a PTEN-dependent mechanism. Sesn2 deletion or knockdown sensitizes squamous cell carcinoma (SCC) cells to 5-fluorouracil-induced apoptosis and melanoma cells to UVB- and vemurafenib-induced apoptosis. In mice Sesn2 knockdown suppresses tumor growth from injected human SCC and melanoma cells. Last, as compared with normal skin, Sesn2 is up-regulated in both human skin SCC and melanoma. Our findings demonstrate that Sesn2 promotes AKT activation and survival in response to UVB stress and chemotherapeutics and suggest that Sesn2 is oncogenic in skin SCC and melanoma.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 6
    Publication Date: 2015-09-02
    Description: The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro, and xenograft growth in vivo. Pertuzumab also potentiated the effects of MEK inhibitor on WT/WT melanoma growth in vitro and in vivo. These findings demonstrate that targeting ErbB3–ErbB2 signaling in a cohort of WT/WT melanomas leads to tumor growth reduction. Together, these studies support the rationale to target the NRG1–ErbB3–ErbB2 axis as a novel treatment strategy in a subset of cutaneous melanomas. Cancer Res; 75(17); 3554–67. ©2015 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 7
    Publication Date: 2015-10-03
    Description: Rapidly accelerated fibrosarcoma (RAF) inhibitors are first-line treatments for patients harboring V600E/K mutant BRAF melanoma. Although RAF inhibitors produce high response rates, the degree of tumor regression is heterogeneous. Compensatory/adaptive responses to targeted inhibitors are frequently initiated by the activation of growth factor receptor tyrosine kinases, including ErbB3, and factors from the tumor microenvironment may play an important role. We have shown previously that mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF) melanoma cells have enhanced activation of ErbB3 following RAF inhibition. However, the source of neuregulin 1 (NRG1), the ligand for ErbB3, is unknown. In this study, we demonstrate that NRG1 is highly expressed by dermal fibroblasts and cancer-associated fibroblasts (CAFs) isolated from mutant BRAF melanomas. Conditioned medium from fibroblasts and CAFs enhanced ErbB3 pathway activation and limited RAF inhibitor cytotoxicity in V600 mutant BRAF-harboring melanomas. Targeting the ErbB3/ErbB2 pathway partially reversed the protective effects of fibroblast/CAF-derived NRG1 on cell growth properties of RAF inhibitor-treated melanoma cells. These findings support the idea that NRG1, acting in a paracrine manner, promotes resistance to RAF inhibitors and emphasize that targeting the ErbB3/ErbB2 pathway will likely improve the efficacy of RAF inhibitors for mutant BRAF melanoma patients.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 8
    Publication Date: 2015-09-05
    Description: Metastatic melanoma is an aggressive and deadly disease. The chemokine receptor CXCR4 is active in melanoma metastasis, although the mechanism for the promotion and maintenance of CXCR4 expression in these cells is mostly unknown. Here, we find melanoma cells express two CXCR4 isoforms, the common version and a variant that is normally restricted to cells during development or to mature blood cells. CXCR4 expression is driven through a highly conserved intronic enhancer element by the transcription factors PAX3 and FOXD3. Inhibition of these transcription factors slows melanoma cell growth, migration, and motility, as well as reduces CXCR4 expression. Overexpression of these transcription factors drives the production of increased CXCR4 levels. Loss of PAX3 and FOXD3 transcription factor activity results in a reduction in cell motility, migration, and chemotaxis, all of which are rescued by CXCR4 overexpression. Here, we discover a molecular pathway wherein PAX3 and FOXD3 promote CXCR4 gene expression in melanoma.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 9
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    The American Association for Cancer Research (AACR)
    Publication Date: 2015-07-02
    Description: Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, respectively, overcome resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. Uveal melanoma xenografts growing in the liver in vivo and a subset of liver metastases of uveal melanoma patients express activated forms of ERBB2 (the coreceptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic uveal melanoma. Cancer Res; 75(13); 2737–48. ©2015 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 10
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    The American Association for Cancer Research (AACR)
    Publication Date: 2016-04-02
    Description: Targeted therapies have advanced the treatment options for cutaneous melanoma, but many patients will progress on drug. Patient-derived xenografts (PDX) can be used to recapitulate therapy-resistant tumors. Furthermore, PDX modeling can be utilized in combination with targeted sequencing and phosphoproteomic platforms, providing preclinical basis for second-line targeted inhibitor strategies. Clin Cancer Res; 22(7); 1550–2. ©2016 AACR . See related article by Krepler et al., p. 1592
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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