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  1. AU="Thomas G. Meikle"
  2. AU="Mummery, C J"
  3. AU="Krantz, Emily"
  4. AU="Bedoya-Arias, Juan E"
  5. AU="Zhou, Heyang"
  6. AU=Latson Larry A
  7. AU=Alhuzimi Eman
  8. AU="Wuerzberger-Davis, Shelly M"
  9. AU="Clippinger, Amy J"
  10. AU="M. S. Islam"
  11. AU="Borrego-Jiménez, Jaime"
  12. AU="Kaoru Dohi"
  13. AU="Tornai, Gábor J"
  14. AU="D'Avella, Christopher"
  15. AU="Lim, Boon L."
  16. AU="Heselden, Marie"
  17. AU=Dias?Polak David
  18. AU="Shahid Umar"
  19. AU="Abu-Shmais, Alexandria A"
  20. AU="Takenaka, Haruka"
  21. AU="Bramley, Andrea"
  22. AU="Sang Hong Lee"

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  1. Artikel ; Online: Metabolic phenotyping of BMI to characterize cardiometabolic risk

    Habtamu B. Beyene / Corey Giles / Kevin Huynh / Tingting Wang / Michelle Cinel / Natalie A. Mellett / Gavriel Olshansky / Thomas G. Meikle / Gerald F. Watts / Joseph Hung / Jennie Hui / Gemma Cadby / John Beilby / John Blangero / Eric K. Moses / Jonathan E. Shaw / Dianna J. Magliano / Peter J. Meikle

    Nature Communications, Vol 14, Iss 1, Pp 1-

    evidence from large population-based cohorts

    2023  Band 19

    Abstract: Abstract Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). Conversely, not all obese individuals present with ... ...

    Abstract Abstract Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). Conversely, not all obese individuals present with metabolic disorders giving rise to the concept of “metabolically healthy obese”. We use lipidomic-based models for BMI to calculate a metabolic BMI score (mBMI) as a measure of metabolic dysregulation associated with obesity. Using the difference between mBMI and BMI (mBMIΔ), we identify individuals with a similar BMI but differing in their metabolic health and disease risk profiles. Exercise and diet associate with mBMIΔ suggesting the ability to modify mBMI with lifestyle intervention. Our findings show that, the mBMI score captures information on metabolic dysregulation that is independent of the measured BMI and so provides an opportunity to assess metabolic health to identify “at risk” individuals for targeted intervention and monitoring.
    Schlagwörter Science ; Q
    Thema/Rubrik (Code) 796
    Sprache Englisch
    Erscheinungsdatum 2023-10-01T00:00:00Z
    Verlag Nature Portfolio
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel: Crystallization of Femtoliter Surface Droplet Arrays Revealed by Synchrotron Small-Angle X-ray Scattering

    Dyett, Brendan / Amy Logan / Charlotte E. Conn / Haitao Yu / Jamie Strachan / Lei Bao / Lisa Zychowski / Miaosi Li / Nigel Kirby / Shuhua Peng / Thomas G. Meikle / Xuehua Zhang

    Langmuir. 2018 July 18, v. 34, no. 32

    2018  

    Abstract: The crystallization of oil droplets is critical in the processing and storage of lipid-based food and pharmaceutical products. Arrays of femtoliter droplets on a surface offer a unique opportunity to study surfactant-free colloidlike systems. In this ... ...

    Abstract The crystallization of oil droplets is critical in the processing and storage of lipid-based food and pharmaceutical products. Arrays of femtoliter droplets on a surface offer a unique opportunity to study surfactant-free colloidlike systems. In this work, the crystal growth process in these confined droplets was followed by cooling a model lipid (trimyristin) from a liquid state utilizing synchrotron small-angle X-ray scattering (SAXS). The measurements by SAXS demonstrated a reduced crystallization rate and a greater degree of supercooling required to trigger lipid crystallization in droplets compared to those of bulk lipids. These results suggest that surface droplets crystallize in a stochastic manner. Interestingly, the crystallization rate is slower for larger femtoliter droplets, which may be explained by the onset of crystallization from the three-phase contact line. The larger surface nanodroplets exhibit a smaller ratio of droplet volume to the length of three-phase contact line and hence a slower crystallization rate.
    Schlagwörter crystallization ; droplets ; drugs ; lipids ; liquids ; models ; oils ; small-angle X-ray scattering ; supercooling
    Sprache Englisch
    Erscheinungsverlauf 2018-0718
    Umfang p. 9470-9476.
    Erscheinungsort American Chemical Society
    Dokumenttyp Artikel
    ZDB-ID 2005937-1
    ISSN 1520-5827 ; 0743-7463
    ISSN (online) 1520-5827
    ISSN 0743-7463
    DOI 10.1021/acs.langmuir.8b01252
    Datenquelle NAL Katalog (AGRICOLA)

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  3. Artikel ; Online: Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer

    Blossom Mak / Hui-Ming Lin / Edmond M. Kwan / Heidi Fettke / Ben Tran / Ian D. Davis / Kate Mahon / Martin R. Stockler / Karen Briscoe / Gavin Marx / Alison Zhang / Megan Crumbaker / Winston Tan / Kevin Huynh / Thomas G. Meikle / Natalie A. Mellett / Andrew J. Hoy / Pan Du / Jianjun Yu /
    Shidong Jia / Anthony M. Joshua / David J. Waugh / Lisa M. Butler / Manish Kohli / Peter J. Meikle / Arun A. Azad / Lisa G. Horvath

    BMC Medicine, Vol 20, Iss 1, Pp 1-

    2022  Band 14

    Abstract: Abstract Background Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration- ... ...

    Abstract Abstract Background Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. Methods We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. Results The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59–3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. Conclusions Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
    Schlagwörter Androgen receptor ; Biomarker ; Castration-resistant prostate cancer ; Genomics ; Lipid ; PI3K ; Medicine ; R
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2022-03-01T00:00:00Z
    Verlag BMC
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Overcoming enzalutamide resistance in metastatic prostate cancer by targeting sphingosine kinase

    Hui-Ming Lin / Blossom Mak / Nicole Yeung / Kevin Huynh / Thomas G. Meikle / Natalie A. Mellett / Edmond M. Kwan / Heidi Fettke / Ben Tran / Ian D. Davis / Kate L. Mahon / Alison Zhang / Martin R. Stockler / Karen Briscoe / Gavin Marx / Megan Crumbaker / Phillip D. Stricker / Pan Du / Jianjun Yu /
    Shidong Jia / Tahlia Scheinberg / Michael Fitzpatrick / Paul Bonnitcha / David R. Sullivan / Anthony M. Joshua / Arun A. Azad / Lisa M. Butler / Peter J. Meikle / Lisa G. Horvath

    EBioMedicine, Vol 72, Iss , Pp 103625- (2021)

    2021  

    Abstract: Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20–30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to ... ...

    Abstract Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20–30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. Methods: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). Findings: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5–3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4–36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity. Interpretation: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors. Funding: None.
    Schlagwörter Metastatic prostate cancer ; Sphingosine kinase ; Enzalutamide ; Ceramide ; Medicine ; R ; Medicine (General) ; R5-920
    Thema/Rubrik (Code) 500
    Sprache Englisch
    Erscheinungsdatum 2021-10-01T00:00:00Z
    Verlag Elsevier
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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