Kooperativer Bibliotheksverbund

Berlin Brandenburg


Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

  • 1
    In: European Journal of Haematology, September 2016, Vol.97(3), pp.239-244
    Description: Byline: Nicole Degwert, Emily Latuske, Gabi Vohwinkel, Hauke Stamm, Marianne Klokow, Carsten Bokemeyer, Walter Fiedler, Jasmin Wellbrock Keywords: Acute myeloid leukaemia; hypoxia; drug resistance; deoxycytidine kinase; hypoxia-inducible factor 1 alpha Abstract Objectives Leukaemia initiating cells reside within specialised niches in the bone marrow where they undergo complex interactions with different stromal cell types. The bone marrow niche is characterised by a low oxygen content resulting in high expression of hypoxia-inducible factor 1 [alpha] in leukaemic cells conferring a negative prognosis to patients with acute myeloid leukaemia (AML). Methods and Results In the current study, we investigated the impact of hypoxic vs. normoxic conditions on the sensitivity of AML cell lines and primary AML blasts to cytarabine. AML cells cultured under 6% oxygen were significantly more resistant against cytarabine compared to cells cultured under normoxic conditions in proliferation and colony-formation assays. Interestingly upon cultivation under hypoxia, the expression of the cytarabine-activating enzyme deoxycytidine kinase was downregulated in all analysed AML cell lines and primary AML samples representing a possible mechanism for resistance to chemotherapy. Furthermore, the downregulation of deoxycytidine kinase could be associated with hypoxia-inducible factor 1 [alpha] as treatment with its inhibitor BAY87-2243 hampered the downregulation of deoxycytidine kinase expression under hypoxic conditions. Conclusions In conclusion, our data reveal that hypoxia-induced downregulation of deoxycytidine kinase represents one stroma-cell-independent mechanism of drug resistance to cytarabine in acute myeloid leukaemia. Article Note: Contributed equally to the work.
    Keywords: Acute Myeloid Leukaemia ; Hypoxia ; Drug Resistance ; Deoxycytidine Kinase ; Hypoxia‐Inducible Factor 1 Alpha
    ISSN: 0902-4441
    E-ISSN: 1600-0609
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: Lung, August 2015, Vol.193(4), pp.567-70
    Description: Gremlin-1, an intrinsic antagonist of bone morphogenetic protein (BMP) signaling, has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, it is unknown whether gremlin-1 can be detected in the circulation of PAH patients and whether it is associated with patients' functional status and outcome. With a mean level of 242 ± 24 ng/ml, gremlin-1 levels of 31 PAH patients were significantly elevated compared to 151 ± 18 ng/ml in 15 age- and gender-matched healthy subject (p = 0.016). In PAH patients, increasing gremlin-1 levels correlated with N-terminal prohormone of brain natriuretic peptide levels (r = 0.608, p 〈 0.001) and inversely with the 6-minute walking distance (r = -0.412, p = 0.029). Furthermore, gremlin-1 significantly stratified survival in PAH patients (p = 0.015). Gremlin-1 may represent a new biomarker for PAH which can be linked directly to the underlying pathomechanism. Elevated levels of gremlin-1 are associated with patients' functional status and survival, thus gremlin-1 neutralization could represent a potential therapeutic strategy to increase BMPR2 signaling.
    Keywords: Hypertension, Pulmonary -- Blood ; Intercellular Signaling Peptides and Proteins -- Blood
    ISSN: 03412040
    E-ISSN: 1432-1750
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: Cellular Signalling, February 2015, Vol.27(2), pp.373-381
    Description: The Hedgehog pathway plays an important role in the pathogenesis of several tumor types, including esophageal cancer. In our study, we show an expression of the ligand Indian hedgehog (Ihh) and its downstream mediator Gli-1 in primary resected adenocarcinoma tissue by immunohistochemistry and quantitative PCR in fifty percent of the cases, while matching healthy esophagus mucosa was negative for both proteins. Moreover, a functionally important regulation of Gli-1 by ErbB2–PI3K–mTORC signaling as well as a Gli-1-dependent regulation of Ihh in the ErbB2 amplified esophageal adenocarcinoma cell line OE19 was observed. Treatment of OE19 cells with the Her2 antibody trastuzumab, the PI3K–mTORC1 inhibitor NVP BEZ235 (BEZ235) or the knockdown of Akt1 resulted in a downregulation of Gli-1 and Ihh as well as in a reduction of viable OE19 cells . Interestingly, the Hedgehog receptor Smo, which acts upstream of Gli-1, was not expressed in OE19 cells and in the majority of primary human esophageal adenocarcinoma, suggesting a non-canonical upregulation of Gli-1 expression by the ErbB2–PI3K axis. To translate our findings into a therapeutic concept, we targeted ErbB2–PI3K–mTORC1 by trastuzumab and BEZ235, combining both compounds with the Gli-1/2 inhibitor GANT61. The triple combination led to significantly stronger reduction of tumor cell viability than cisplatinum or each biological alone. Therefore, concomitant blockage of the ErbB2–PI3K pathway and the Hedgehog downstream mediator Gli-1 may provide a new therapeutic strategy for esophageal cancer.
    Keywords: Esophageal Cancer ; Hedgehog ; Gli ; Non-Canonical ; Erbb2–Akt ; Biology
    ISSN: 0898-6568
    E-ISSN: 1873-3913
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages