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  • 1
    Publication Date: 2016-06-16
    Description: In many cancers, aberrant Notch activity has been demonstrated to play a role in the initiation and maintenance of the neoplastic phenotype and in cancer stem cells, which may allude to its additional involvement in metastasis and resistance to therapy. Therefore, Notch is an exceedingly attractive therapeutic target in cancer, but the full range of potential targets within the pathway has been underexplored. To date, there are no small-molecule inhibitors that directly target the intracellular Notch pathway or the assembly of the transcriptional activation complex. Here, we describe an in vitro assay that quantitatively measures the assembly of the Notch transcriptional complex on DNA. Integrating this approach with computer-aided drug design, we explored potential ligand-binding sites and screened for compounds that could disrupt the assembly of the Notch transcriptional activation complex. We identified a small-molecule inhibitor, termed Inhibitor of Mastermind Recruitment-1 (IMR-1), that disrupted the recruitment of Mastermind-like 1 to the Notch transcriptional activation complex on chromatin, thereby attenuating Notch target gene transcription. Furthermore, IMR-1 inhibited the growth of Notch-dependent cell lines and significantly abrogated the growth of patient-derived tumor xenografts. Taken together, our findings suggest that a novel class of Notch inhibitors targeting the transcriptional activation complex may represent a new paradigm for Notch-based anticancer therapeutics, warranting further preclinical characterization. Cancer Res; 76(12); 3593–603. ©2016 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 2
    Publication Date: 2018-05-08
    Description: Cell cycle quiescence is critical for hematopoietic stem cell (HSC) maintenance. TGF-β signaling in bone marrow niche has been identified in regulating HSC quiescence; however, the intrinsic regulatory mechanisms remain unclear. This study reports that Shp-1 knockout HSCs have attenuated quiescence and impaired long-term self-renewal. SHP-1–activated HSCs are surrounded by megakaryocytes, which regulate HSC quiescence by producing TGF-β1. Mechanistically, SHP-1 interacts with the immunoreceptor tyrosine-based inhibition motif on TGF-β receptor 1 and is critical for TGF-β signaling activation in HSCs. Functionally, Shp-1 knockout HSCs do not respond to TGF-β–enforced HSC quiescence regulation, both in vitro and in vivo. Therefore, we identify TGF-β–SHP-1 as a novel intrinsic regulatory mechanism for HSC quiescence maintenance.
    Keywords: Stem Cells & Regeneration, Hematopoiesis
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 3
    Publication Date: 2018-06-02
    Description: Objective This study aims to understand the age patterns of smoking initiation during adolescence and young adulthood in South-West China, where the prevalence of tobacco use is reported as the highest in the country. Design A cross-sectional study. Setting The data were derived from the China National Nutrition and Health Survey in Yunnan Province, South-West China (2010–2012). Participants A total of 4801 participants aged 15–65 years were included. Primary outcome measures A survival model was used to estimate the hazard of smoking initiation by age and log-rank test was used to compare the hazard curves across subgroups (men/women, urban/rural, Han Chinese/ethnic minority). Results The prevalence of current smoking among men and women were 60.4% (95% CI 58.2% to 62.6%) and 5.1% (95% CI 4.3% to 5.9%), respectively. Smoking was more prevalent among men and women of lower education and less income, as well as rural and ethnic minority women. Among the current smokers, cigarette (80.7%) was the most commonly used tobacco product, followed by waterpipe (10.8%) and pipe tobacco (8.5%). The hazards of smoking initiation were low for both men and women before the age of 15 years (1% for men and 0.05% for women); and the hazards increased quickly from age 15 years and peaked at 19years (21.5% for men and 1.0% for women). Rural and ethnic minority women were at higher risk of smoking initiation than their counterparts between 15 years and 19 years of age ( 2 =44.8, p〈0.01; 2 =165.2, p〈0.01) and no such difference was found in men. Conclusions Findings of this study underscore the importance to implement tobacco prevention interventions among older teens and young adults in South-West China, especially for rural and ethnic minority women.
    Keywords: Open access, Smoking and tobacco
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 4
    Publication Date: 2014-11-01
    Description: Esophageal adenocarcinoma ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the Western population over the last decades. Data presented herein strongly suggest that Notch signaling is critical for esophageal adenocarcinoma and underlies resistance to chemotherapy. We present evidence that Notch signaling drives a cancer stem cell phenotype by regulating genes that establish stemness. Using patient-derived xenograft models, we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth. Moreover, we demonstrate that Notch activity in a patient's ultrasound-assisted endoscopic–derived biopsy might predict outcome to chemotherapy. Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating esophageal adenocarcinoma, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in esophageal adenocarcinoma treatment. Cancer Res; 74(21); 6364–74. ©2014 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 5
    Publication Date: 2014-12-02
    Description: Purpose: Altered expression of heat shock protein 90 alpha (Hsp90α) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90α protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer. Experimental Design: A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90α protein levels for association with tumor stages and treatment responses, respectively, were performed. Results: The average plasma levels of Hsp90α protein in patients with lung cancer were significantly higher than in healthy controls ( P 〈 0.0001). Plasma levels of Hsp90α protein in patients with advanced lung cancer (stage III–IV) were higher than in patients with early-stage lung cancer (stage I–II; P 〈 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695–0.749) and 78.70% (95% CI, 0.761–0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90α protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups ( P 〈 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy ( P 〈 0.0001). Conclusions: This study demonstrated that plasma Hsp90α protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy. Clin Cancer Res; 20(23); 6016–22. ©2014 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 6
    Publication Date: 2014-09-03
    Description: The Notch signaling pathway governs many distinct cellular processes by regulating transcriptional programs. The transcriptional response initiated by Notch is highly cell context dependent, indicating that multiple factors influence Notch target gene selection and activity. However, the mechanism by which Notch drives target gene transcription is not well understood. Herein, we identify and characterize a novel Notch-interacting protein, Notch activation complex kinase (NACK), which acts as a Notch transcriptional coactivator. We show that NACK associates with the Notch transcriptional activation complex on DNA, mediates Notch transcriptional activity, and is required for Notch-mediated tumorigenesis. We demonstrate that Notch1 and NACK are coexpressed during mouse development and that homozygous loss of NACK is embryonic lethal. Finally, we show that NACK is also a Notch target gene, establishing a feed-forward loop. Thus, our data indicate that NACK is a key component of the Notch transcriptional complex and is an essential regulator of Notch-mediated tumorigenesis and development. Cancer Res; 74(17); 4741–51. ©2014 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 7
    Publication Date: 2014-12-16
    Description: E-proteins are TCR-sensitive transcription factors essential for intrathymic T cell transitions. Here, we show that deletion of E-proteins leads to both enhanced peripheral TGF-β–induced regulatory T (iT reg) cell and thymic naturally arising T reg cell (nT reg cell) differentiation. In contrast, deletion of Id proteins results in reduced nT reg cell differentiation. Mechanistic analysis indicated that decreased E-protein activity leads to de-repression of signaling pathways that are essential to Foxp3 expression. Decreased E-protein binding to an IL-2Rα enhancer locus facilitated TCR-induced IL-2Rα expression. Similarly, decreased E-protein activity facilitated TCR-induced NF-B activation and generation of c-Rel. Consistent with this, microarray analysis indicated that cells with E-protein depletion that are not yet expressing Foxp3 exhibit activation of the IL-2 and NF-B signaling pathways as well as enhanced expression of many of the genes associated with Foxp3 induction. Finally, studies using Nur77-GFP mice to monitor TCR signaling showed that TCR signaling strength sufficient to induce Foxp3 differentiation is accompanied by down-regulation of E-protein levels. Collectively, these data suggest that TCR stimulation acts in part through down-regulation of E-protein activity to induce T reg cell lineage development.
    Keywords: Lymphocyte Biology
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 8
    Publication Date: 2014-07-16
    Description: Invasion and dissemination of medulloblastoma within the central nervous system is the principal factor predicting medulloblastoma treatment failure and death. Netrin-1 is an axon guidance factor implicated in tumor and vascular biology, including in invasive behaviors. We found that exogenous netrin-1 stimulated invasion of human medulloblastoma cells and endothelial cells in contrast to VEGF-A, which promoted invasion of endothelial cells but not medulloblastoma cells. Furthermore, medulloblastoma cells expressed endogenous netrin-1 along with its receptors, neogenin and UNC5B. Blockades in endogenous netrin-1, neogenin, or UNC5B reduced medulloblastoma invasiveness. Neogenin blockade inhibited netrin-1–induced endothelial cells tube formation and recruitment of endothelial cells into Matrigel plugs, two hallmarks of angiogenesis. In patients with pediatric medulloblastoma, netrin-1 mRNA levels were increased 1.7-fold in medulloblastoma tumor specimens compared with control specimens from the same patient. Immunohistochemical analyses showed that netrin-1 was elevated in medulloblastoma tumors versus cerebellum controls. Notably, urinary levels of netrin-1 were 9-fold higher in patients with medulloblastoma compared with control individuals. Moreover, urinary netrin-1 levels were higher in patients with invasive medulloblastoma compared with patients with noninvasive medulloblastoma. Finally, we noted that urinary netrin-1 levels diminished after medulloblastoma resection in patients. Our results suggest netrin-1 is a candidate biomarker capable of detecting an invasive, disseminated phenotype in patients with medulloblastoma and predicting their disease status. Cancer Res; 74(14); 3716–26. ©2014 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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  • 9
  • 10
    Publication Date: 2015-11-03
    Description: The serine/threonine kinase LKB1 is a well-characterized tumor suppressor that governs diverse cellular processes, including growth, polarity, and metabolism. Somatic-inactivating mutations in LKB1 are observed in about 15% to 30% of non–small cell lung cancers (NSCLC). LKB1 inactivation confers lung adenocarcinomas (ADC) with malignant features that remain refractory to therapeutic intervention. YAP activation has been linked to LKB1 deficiency, but the role of YAP in lung ADC formation and progression is uncertain. In this study, we showed that ectopic expression of YAP in type II alveolar epithelial cells led to hyperplasia in mouse lungs. YAP overexpression in the KrasG12D lung cancer mouse model accelerated lung ADC progression. Conversely, YAP deletion dramatically delayed the progression of lung ADC in LKB1-deficient KrasG12D mice. Mechanistic studies identified the antiapoptotic oncoprotein survivin as the downstream mediator of YAP responsible for promoting malignant progression of LKB1-deficient lung ADC. Collectively, our findings identify YAP as an important contributor to lung cancer progression, rationalizing YAP inhibition in the context of LKB1 deficiency as a therapeutic strategy to treat lung ADC. Cancer Res; 75(21); 4450–7. ©2015 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
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