| 11. |
- Kroeze, Leonie I., et al.
(författare)
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Evaluation of a Hybrid Capture-Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes
- 2020
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Ingår i: Journal of Molecular Diagnostics. - : Elsevier. - 1525-1578 .- 1943-7811. ; 22:6, s. 757-769
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Tidskriftsartikel (refereegranskat)abstract
- Stratification of patients for targeted and immune-based therapies requires extensive genomic profiling that enables sensitive detection of clinically relevant variants and interrogation of biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI). Detection of single and multiple nucleotide variants, copy number variants, MSI, and TMB was evaluated using a commercially available next-generation sequencing panel containing 523 cancer-related genes (1.94 megabases). Analysis of formalin-fixed, paraffin-embedded tissue sections and cytologic material from 45 tumor samples showed that all previously known MSI-positive samples (n = 7), amplifications (n = 9), and pathogenic variants (n = 59) could be detected. TMB and MSI scores showed high intralaboratory and interlaboratory reproducibility (eight samples tested in 11 laboratories). For reliable TMB analysis, 20 ng DNA was shown to be sufficient, even for relatively poor-quality samples. A minimum of 20% neoplastic cells was required to minimize variations in TMB values induced by chromosomal instability or tumor heterogeneity. Subsequent analysis of 58 consecutive lung cancer samples in a diagnostic setting was successful and revealed sufficient somatic mutations to generate mutational signatures in 14 cases. In conclusion, the 523-gene assay can be applied for evaluation of multiple DNA-based biomarkers relevant for treatment selection.
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| 12. |
- Lavazais, S, et al.
(författare)
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IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases
- 2023
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 15:683, s. eabj3289-
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23–, IL-33–, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.
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| 13. |
- Liu, Chang, et al.
(författare)
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SN 2022joj : A Peculiar Type Ia Supernova Possibly Driven by an Asymmetric Helium-shell Double Detonation
- 2023
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 958:2
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Tidskriftsartikel (refereegranskat)abstract
- We present observations of SN 2022joj, a peculiar Type Ia supernova discovered by the Zwicky Transient Facility. SN 2022joj exhibits an unusually red g ZTF - r ZTF color at early times and a rapid blueward evolution afterward. Around maximum brightness, SN 2022joj shows a high luminosity ( MgZTF,max similar or equal to-19.7 mag), a blue broadband color (g ZTF - r ZTF similar or equal to -0.2 mag), and shallow Si ii absorption lines, consistent with those of overluminous, SN 1991T-like events. The maximum-light spectrum also shows prominent absorption around 4200 angstrom, which resembles the Ti ii features in subluminous, SN 1991bg-like events. Despite the blue optical-band colors, SN 2022joj exhibits extremely red ultraviolet minus optical colors at maximum luminosity (u - v similar or equal to 0.6 mag and uvw1 - v similar or equal to 2.5 mag), suggesting a suppression of flux at similar to 2500-4000 angstrom. Strong C ii lines are also detected at peak. We show that these unusual spectroscopic properties are broadly consistent with the helium-shell double detonation of a sub-Chandrasekhar mass (M similar or equal to 1 M circle dot) carbon/oxygen white dwarf from a relatively massive helium shell (M s similar or equal to 0.04-0.1 M circle dot), if observed along a line of sight roughly opposite to where the shell initially detonates. None of the existing models could quantitatively explain all the peculiarities observed in SN 2022joj. The low flux ratio of [Ni ii] lambda 7378 to [Fe ii] lambda 7155 emission in the late-time nebular spectra indicates a low yield of stable Ni isotopes, favoring a sub-Chandrasekhar mass progenitor. The significant blueshift measured in the [Fe ii] lambda 7155 line is also consistent with an asymmetric chemical distribution in the ejecta, as is predicted in double-detonation models.
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| 14. |
- Mansourian, A, et al.
(författare)
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Showcase of Existing Active Teaching Practices
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report presents showcases of active teaching and learning in spatial data infrastructure education in the SPIDER partner universities. It includes detailed descriptions of the practices that have been implemented, as well as the results of the evaluation of the practices from an active teaching learning perspective.
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| 15. |
- Naruse, Mitsuhide, et al.
(författare)
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International multicenter survey on screening and confirmatory testing in primary aldosteronism.
- 2023
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Ingår i: European journal of endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 188:1
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Tidskriftsartikel (refereegranskat)abstract
- Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized.In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated.We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers.Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.
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| 16. |
- Taïeb, David, et al.
(författare)
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Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants : an international expert Consensus statement
- 2024
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Ingår i: Nature Reviews Endocrinology. - : Springer Nature. - 1759-5029 .- 1759-5037. ; 20:3, s. 168-184
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Forskningsöversikt (refereegranskat)abstract
- Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
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