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- Ai, Jiaoyu, et al.
(author)
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Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes
- 2021
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 161:1, s. 318-332
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Journal article (peer-reviewed)abstract
- Background & Aims: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.Methods: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes.Results: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.Conclusions: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.
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| 2. |
- Steingoetter, Andreas, et al.
(author)
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Reference Region-Based Pharmacokinetic Modeling in Quantitative Dynamic Contract-Enhanced MRI Allows Robust Treatment Monitoring in a Rat Liver Tumor Model Despite Cardiovascular Changes
- 2011
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In: Magnetic Resonance in Medicine. - : Wiley. - 1522-2594 .- 0740-3194. ; 65:1, s. 229-238
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Journal article (peer-reviewed)abstract
- In this work, two pharmacokinetic modeling techniques, population arterial input function model, and reference region model, were applied to dynamic contract-enhanced MRI data, to test the influence of a change in heart rate on modeling parameters. A rat population arterial input function was generated by dynamic contrast-enhanced computed tomography measurements using the MR contrast agent gadolinium diethylenetriamine penta-acetic acid. Then, dynamic contract-enhanced MRI was used for treatment monitoring in two groups of hepatocellular carcinoma bearing rats. Whereas group 1 had the same heart rate as animals analyzed for the population arterial input function (263 +/- 20 bpm), group 2 had a higher heart rate (369 +/- 11 bpm) due to a different anesthesia protocol. The pharmacokinetic modeling parameters volume transfer constant K-trans and relative extravascular extracellular space v(e) were calculated with both models and statistically compared. For group 1, good correlation and agreement was found between the models showing no difference in K-trans and v(e) (Delta K-trans:4 +/- 19% and Delta v(e):4 +/- 12%, P = 0.2). In contrast, for group 2, a bias in parameter values for the population arterial input function model was detected (Delta K-trans: -45 +/- 7% and Delta v(e):-31 +/- 7%, P <= 0.001). The presented work underlines the value of the reference region model in longitudinal treatment monitoring and provides a straightforward approach for the generation of a rat population arterial input function. Magn Reson Med 65: 229-238, 2011. (C) 2010 Wiley-Liss, Inc.
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| 3. |
- Tapfer, Arne, et al.
(author)
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X-Ray Phase-Contrast CT of a Pancreatic Ductal Adenocarcinoma Mouse Model
- 2013
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
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Journal article (peer-reviewed)abstract
- To explore the potential of grating-based x-ray phase-contrast computed tomography (CT) for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i) high-resolution synchrotron radiation (SR) imaging and ii) dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i) high-performance imaging for virtual microscopy applications and ii) biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI) were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR) of selected regions of interest (ROI) in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.
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