| 1. |
- Forni, Claudia, et al.
(författare)
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Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors.
- 2009
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Ingår i: Molecular cancer therapeutics. - 1535-7163. ; 8:2, s. 449-57
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Tidskriftsartikel (refereegranskat)abstract
- Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whose alpha, beta, and delta members are master genes of adipogenesis. Recent clinical data indicate a peculiar sensitivity of these tumors to the natural marine compound trabectedin. One hypothesis is that the activity of trabectedin is related to the inactivation of the FUS-CHOP oncogene. We find that trabectedin causes detachment of the FUS-CHOP chimera from targeted promoters. Reverse transcription-PCR and chromatin immunoprecipitation analysis in a MLS line and surgical specimens of MLS patients in vivo show activation of the CAAT/enhancer binding protein-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis. The activity is observed in cells with type 1 but not type 8 fusions. Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. These data provide a rationale for the specific activity of trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.
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| 2. |
- Simón Serrano, Sonia, et al.
(författare)
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Novel Cyclophilin Inhibitor Decreases Cell Proliferation and Tumor Growth in Models of Hepatocellular Carcinoma
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient's life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel cyclophilin inhibitor, NV651, was able to significantly decrease proliferation in a diverse set of HCC cell lines. The exposure of HCC cells to NV651 caused an accumulation of cells during mitosis and consequent accumulation in the G2/M phase of the cell cycle. NV651 reduced tumor growth in vivo using an HCC xenograft model without affecting the body weights of the animals. The safety aspects of NV651 were also confirmed in primary human hepatocytes without any cytotoxic effects. Based on the results obtained in this study, we propose NV651 as a potential treatment strategy for HCC.
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| 3. |
- Simón Serrano, Sonia, et al.
(författare)
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Synergistic Effects of Sanglifehrin-Based Cyclophilin Inhibitor NV651 with Cisplatin in Hepatocellular Carcinoma
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:19
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC), commonly diagnosed at an advanced stage, is the most common primary liver cancer. Owing to a lack of effective HCC treatments and the commonly acquired chemoresistance, novel therapies need to be investigated. Cyclophilins—intracellular proteins with peptidyl-prolyl isomerase activity—have been shown to play a key role in therapy resistance and cell proliferation. Here, we aimed to evaluate changes in the gene expression of HCC cells caused by cyclophilin inhibition in order to explore suitable combination treatment approaches, including the use of chemoagents, such as cisplatin. Our results show that the novel cyclophilin inhibitor NV651 decreases the expression of genes involved in several pathways related to the cancer cell cycle and DNA repair. We evaluated the potential synergistic effect of NV651 in combination with other treatments used against HCC in cisplatin-sensitive cells. NV651 showed a synergistic effect in inhibiting cell proliferation, with a significant increase in intrinsic apoptosis in combination with the DNA crosslinking agent cisplatin. This combination also affected cell cycle progression and reduced the capacity of the cell to repair DNA in comparison with a single treatment with cisplatin. Based on these results, we believe that the combination of cisplatin and NV651 may provide a novel approach to HCC treatment.
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| 4. |
- Soffitta, Paolo, et al.
(författare)
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XIPE : the X-ray imaging polarimetry explorer
- 2013
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Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 36:3, s. 523-567
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Tidskriftsartikel (refereegranskat)abstract
- X-ray polarimetry, sometimes alone, and sometimes coupled to spectral and temporal variability measurements and to imaging, allows a wealth of physical phenomena in astrophysics to be studied. X-ray polarimetry investigates the acceleration process, for example, including those typical of magnetic reconnection in solar flares, but also emission in the strong magnetic fields of neutron stars and white dwarfs. It detects scattering in asymmetric structures such as accretion disks and columns, and in the so-called molecular torus and ionization cones. In addition, it allows fundamental physics in regimes of gravity and of magnetic field intensity not accessible to experiments on the Earth to be probed. Finally, models that describe fundamental interactions (e.g. quantum gravity and the extension of the Standard Model) can be tested. We describe in this paper the X-ray Imaging Polarimetry Explorer (XIPE), proposed in June 2012 to the first ESA call for a small mission with a launch in 2017. The proposal was, unfortunately, not selected. To be compliant with this schedule, we designed the payload mostly with existing items. The XIPE proposal takes advantage of the completed phase A of POLARIX for an ASI small mission program that was cancelled, but is different in many aspects: the detectors, the presence of a solar flare polarimeter and photometer and the use of a light platform derived by a mass production for a cluster of satellites. XIPE is composed of two out of the three existing JET-X telescopes with two Gas Pixel Detectors (GPD) filled with a He-DME mixture at their focus. Two additional GPDs filled with a 3-bar Ar-DME mixture always face the Sun to detect polarization from solar flares. The Minimum Detectable Polarization of a 1 mCrab source reaches 14 % in the 2-10 keV band in 10(5) s for pointed observations, and 0.6 % for an X10 class solar flare in the 15-35 keV energy band. The imaging capability is 24 arcsec Half Energy Width (HEW) in a Field of View of 14.7 arcmin x 14.7 arcmin. The spectral resolution is 20 % at 6 keV and the time resolution is 8 mu s. The imaging capabilities of the JET-X optics and of the GPD have been demonstrated by a recent calibration campaign at PANTER X-ray test facility of the Max-Planck-Institut fur extraterrestrische Physik (MPE, Germany). XIPE takes advantage of a low-earth equatorial orbit with Malindi as down-link station and of a Mission Operation Center (MOC) at INPE (Brazil). The data policy is organized with a Core Program that comprises three months of Science Verification Phase and 25 % of net observing time in the following 2 years. A competitive Guest Observer program covers the remaining 75 % of the net observing time.
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| 5. |
- Tavecchio, Michele, et al.
(författare)
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Multi-parametric flow cytometric cell cycle analysis using TO-PRO-3 iodide (TP3): detailed protocols.
- 2008
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Ingår i: Acta histochemica. - : Elsevier BV. - 0065-1281. ; 110:3, s. 232-44
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Tidskriftsartikel (refereegranskat)abstract
- TO-PRO-3 iodide (TP3), a monomeric cyanine nucleic acid stain with a peak absorbance at 642 nm and emission at 661 nm, is best excited by a helium-neon (HeNe) laser (633nm). It was tested in monocytes and different cell lines under conditions of different fixatives, dye concentrations, labeling kinetics and RNAse concentrations for mono-, bi- and tri-parametric flow cytometric cell cycle analysis to establish the best protocol for DNA analysis in terms of G1 peak CV, G2/G1 ratio and minimal amount of debris. A linear increase in G1 peak position was found from 0.1 to 2 microM TP3 concentrations. Fixatives 70% ethanol or 1% methanol-free formaldehyde, followed by 70% ethanol, resulted in the best DNA histograms. Although different protocols were found to be cell-type specific, in general, excellent results were obtained with 30 min incubation with 0.5 microM TP3 plus RNAse in almost all cell lines tested. These data show that TP3 is an alternative method to propidium iodide (PI), the most commonly used DNA-specific probe in flow cytometry. The most important advantage of using TP3 in combination with other fluorochromes, such as fluorescein isothiocyanate (FITC) or phycoerythrin (PE) in bi- or tri-parametric flow cytometric analysis, is that there is no need for fluorescence compensation for the TP3 signals.
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