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- Ali, M, et al.
(author)
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T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
- 2022
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In: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 40:4, s. 488-
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Journal article (peer-reviewed)abstract
- Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
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| 5. |
- Knobler, R., et al.
(author)
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Guidelines on the use of extracorporeal photopheresis
- 2014
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In: Journal of the European Academy of Dermatology and Venereology. - : Wiley-Blackwell. - 0926-9959 .- 1468-3083. ; 28:s1, s. 1-37
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Journal article (peer-reviewed)abstract
- BackgroundAfter the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. Materials and methodsIn order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. Results and conclusionThese guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.
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- Saravia, M. E., et al.
(author)
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Morphological identification of Streptococcus mutans and Streptococcus sobrinus in SB-20M culture medium has efficiency comparable to proteomic identification by the MALDI-TOF mass spectrometry technique
- 2020
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In: Archives of Oral Biology. - : Elsevier BV. - 0003-9969. ; 110
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Journal article (peer-reviewed)abstract
- Objectives: The objective of this study was to evaluate the efficiency of SB-20 M culture medium to perform differential morphological identification of S. mutans and S. sobrinus compared to biochemical identification and to proteomic identification by the MALDI-TOF mass spectrometry technique. Material and methods: Unstimulated saliva samples from 266 dental students were seeded on SB-20 M culture medium by the wooden spatula technique. After incubation, S. mutans and S. sobrinus colonies were identified by stereomicroscopy based on their differential morphological characteristics. Following these procedures, 135 colonies with characteristic morphology of S. mutans (89 colonies) and S. sobrinus (46 colonies) were randomly selected, submitted to biochemical identification (biotyping) and proteomic identification by the MALDI-TOF mass spectrometry technique. The results were compared using the Kappa test, with a 5% significance level. Results: All (100%) S. mutans colonies were correctly identified after culture in SB-20 M medium compared to biotyping and proteomic identification. For S. sobrinus, morphological identification in SB-20 M medium was correct for 43 colonies (93.5%) compared to biotyping and proteomic identification. However, there was no statistically significant difference when comparing the capacity to identify S. mutans and S. sobrinus of the three techniques (p < 0.001; K = 0.951). Conclusions: It was concluded that the SB-20 M culture medium for morphological identification of S. mutans and S. sobrinus was highly reliable, being comparable to the MALDI-TOF mass spectrometry technique. Clinical relevance: The efficiency evaluation of identification methods of S. mutans and S. sobrinus is clinically relevant in order to determine caries risk and activity of patients. © 2019 Elsevier Ltd
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- Bonekamp, N. A., et al.
(author)
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Small-molecule inhibitors of human mitochondrial DNA transcription
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588, s. 712-716
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Journal article (peer-reviewed)abstract
- Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system(1-6). The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.
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| 11. |
- Hillen, M., et al.
(author)
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The evolved circumbinary disk of AC Herculis : a radiative transfer, interferometric, and mineralogical study
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 578
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Journal article (peer-reviewed)abstract
- Context. Many post-asymptotic giant branch (post-AGB) stars in binary systems have an infrared (IR) excess arising from a dusty circumbinary disk. The disk formation, current structure, and further evolution are, however, poorly understood. Aims. We aim to constrain the structure of the circumstellar material around the post-AGB binary and RV Tauri pulsator AC Her. We want to constrain the spatial distribution of the amorphous and of the crystalline dust. Methods. We present very high-quality mid-IR interferometric data that were obtained with the MIDI / VLTI instrument. We analyze the MIDI visibilities and di ff erential phases in combination with the full spectral energy distribution, using the MCMax radiative transfer code, to find a good structure model of AC Her's circumbinary disk. We include a grain size distribution and midplane settling of dust self-consistently in our models. The spatial distribution of crystalline forsterite in the disk is investigated with the mid-IR features, the 69 mu m band and the 11.3 mu m signatures in the interferometric data. Results. All the data are well fitted by our best model. The inclination and position angle of the disk are precisely determined at i = 50 +/- 8 degrees and PA = 305 +/- 10 degrees. We firmly establish that the inner disk radius is about an order of magnitude larger than the dust sublimation radius. The best-fit dust grain size distribution shows that significant grain growth has occurred, with a significant amount of mm-sized grains now being settled to the midplane of the disk. A large total dust mass >= 10(-3) M-circle dot is needed to fit the mm fluxes. By assuming alpha(turb) = 0 : 01, a good fit is obtained with a small grain size power law index of 3.25, combined with a small gas / dust ratio <= 10. The resulting gas mass is compatible with recent estimates employing direct gas diagnostics. The spatial distribution of the forsterite is di ff erent from the amorphous dust, as more warm forsterite is needed in the surface layers of the inner disk. Conclusions. The disk in the ACHer system is in a very evolved state, as shown by its small gas/dust ratio and large inner hole. Mid-IR interferometry o ff ers unique constraints, complementary to mid-IR features, for studying the mineralogy in disks. A better uv coverage is needed to constrain in detail the distribution of the crystalline forsterite in the disk of ACHer, but we find strong similarities with the protoplanetary disk HD 100546.
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| 12. |
- Koumpia, E., et al.
(author)
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Optical and near-infrared observations of the Fried Egg Nebula: Multiple shell ejections on a 100 yr timescale from a massive yellow hypergiant
- 2020
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635
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Journal article (peer-reviewed)abstract
- Context. The fate of a massive star during the latest stages of its evolution is highly dependent on its mass-loss rate and geometry and therefore knowing the geometry of the circumstellar material close to the star and its surroundings is crucial. Aims. We aim to provide insight into the nature (i.e. geometry, rates) of mass-loss episodes, and in particular, the connection between the observed asymmetries due to the mass lost in a fast wind or during a previous, prodigious mass-losing phase. In this context, yellow hypergiants offer a good opportunity to study mass-loss events. Methods. We analysed a large set of optical and near-infrared data in spectroscopic and photometric, spectropolarimetric, and interferometric (GRAVITY/VLTI) modes, towards the yellow hypergiant IRAS 17163-3907. We used X-shooter optical observations to determine the spectral type of this yellow hypergiant and we present the first model-independent, reconstructed images of IRAS 17163-3907 at these wavelengths tracing milli-Arcsecond scales. Lastly, we applied a 2D radiative transfer model to fit the dereddened photometry and the radial profiles of published diffraction-limited VISIR images at 8.59 μm, 11.85 μm, and 12.81 μm simultaneously, adopting a revised distance determination using Gaia Data Release 2 measurements. Results. We constrain the spectral type of IRAS 17163-3907 to be slightly earlier than A6Ia (Teffâ ∼â 8500 K). The interferometric observables around the 2 μm window towards IRAS 17163-3907 show that the Brγ emission appears to be more extended and asymmetric than the Naâ » I and the continuum emission. Interestingly, the spectrum of IRAS 17163-3907 around 2 μm shows Mgâ » II emission that is not previously seen in other objects of its class. In addition, Brγ shows variability in a time interval of four months that is not seen towards Naâ » I. Lastly, in addition to the two known shells surrounding IRAS 17163-3907, we report on the existence of a third hot inner shell with a maximum dynamical age of only 30 yr. Conclusions. The 2 μm continuum originates directly from the star and not from hot dust surrounding the stellar object. The observed spectroscopic variability of Brγ could be a result of variability in the mass-loss rate. The interpretation of the presence of Naâ » I emission at closer distances to the star compared to Brγ has been a challenge in various studies. To address this, we examine several scenarios. We argue that the presence of a pseudo-photosphere, which was traditionally considered to be the prominent explanation, is not needed and that it is rather an optical depth effect. The three observed distinct mass-loss episodes are characterised by different mass-loss rates and can inform theories of mass-loss mechanisms, which is a topic still under debate both in theory and observations. We discuss these in the context of photospheric pulsations and wind bi-stability mechanisms.
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| 14. |
- Lombaert, Robin, 1986, et al.
(author)
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Mineralogy of an OH/IR superwind
- 2016
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In: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 728:2
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Conference paper (peer-reviewed)abstract
- The mineralogy of the dense, dusty superwind of OH/IR stars can provide important constraints for understanding the dust formation process as well as the acceleration of the wind. We aim to model the ISO-SWS spectrum of the OH/IR star OH 30.1-0.7 in detail by reproducing the slope of the spectral energy distribution in the continuum regions between 3 and 8 μm and 12 and 15 μm. In addition to metallic Fe, we find that larger amorphous olivine grains of size on the order of 1 μm may also contribute to the continuum emission. We report here on the preliminary model results and discuss their validity given the important assumption of a 1D spherically symmetric stellar wind.
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| 15. |
- Lombaert, Robin, 1986, et al.
(author)
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The Problematically Short Superwind of OH/IR Stars
- 2015
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In: EAS Publications Series. - : EDP Sciences. - 1633-4760 .- 1638-1963. - 9782759819072 ; 71-72, s. 65-70
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Conference paper (peer-reviewed)abstract
- The superwind is believed to be the tool with which stars with an intermediate main-sequence mass between 5 and 8 Me shed most of their stellar mantle to evolve from the asymptotic giant branch (AGB) into the post-AGB and planetary-nebulae stages. For this to work, the superwind duration must be on the order of at least ten thousand years given a mass-loss rate of 10(-4) M-circle dot per year. This contrasts heavily with recent, independent results indicating that the superwind duration may be shorter by an order of magnitude.
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| 17. |
- Vanherp, L, et al.
(author)
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Sensitive bioluminescence imaging of fungal dissemination to the brain in mouse models of cryptococcosis
- 2019
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In: Disease models & mechanisms. - : The Company of Biologists. - 1754-8411 .- 1754-8403. ; 12:6
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Journal article (peer-reviewed)abstract
- Cryptococcus neoformans is a leading cause of fungal brain infections, but the mechanism of dissemination and dynamics of cerebral infection following pulmonary disease are poorly understood. To address these questions, non-invasive techniques that can study the dynamic processes of disease development and progression in living animal models or patients are required. As such, bioluminescence imaging (BLI) has emerged as a powerful tool to evaluate the spatial and temporal distribution of infection in living animals. We aimed at studying the time profile of the dissemination of cryptococcosis from the lung to the brain in murine models by engineering the first bioluminescent C. neoformans KN99α strain expressing a sequence-optimized red-shifted luciferase. The high pathogen-specificity and sensitivity of BLI was complemented with the three-dimensional anatomical information from micro-computed tomography (CT) of the lung and magnetic resonance imaging (MRI) of the brain. These non-invasive imaging techniques provided longitudinal read-outs on the spatial and temporal distribution of infection following intravenous, intranasal or endotracheal routes of inoculation. Furthermore, the imaging results correlated strongly with the fungal load in the respective organs. By obtaining dynamic and quantitative information about the extent and timing of brain infections for individual animals, we found that dissemination to the brain after primary infection of the lung is likely a late-stage event with a time frame that is variable between animals. This novel tool in Cryptococcus research can aid the identification of host and pathogen factors involved in this process and supports development of novel preventive or therapeutic approaches.
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