| 1. |
- Fleming, Cassandra L., et al.
(författare)
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All-photonic kinase inhibitors: light-controlled release-and-report inhibition
- 2024
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Ingår i: CHEMICAL SCIENCE. - 2041-6520 .- 2041-6539. ; 15:18, s. 6897-6905
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Tidskriftsartikel (refereegranskat)abstract
- Light-responsive molecular tools targeting kinases affords one the opportunity to study the underlying cellular function of selected kinases. In efforts to externally control lymphocyte-specific protein tyrosine kinase (LCK) activity, the development of release-and-report LCK inhibitors is described, in which (i) the release of the active kinase inhibitor can be controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the active kinase inhibitor. This introduces an unprecedented all-photonic method for users to both control and monitor real-time inhibitory activity. A functional cellular assay demonstrated light-mediated LCK inhibition in natural killer cells. The use of coumarin-derived caging groups resulted in rapid cellular uptake and non-specific intracellular localisation, while a BODIPY-derived caging group predominately localised in the cellular membrane. This concept of release-and-report inhibitors has the potential to be extended to other biorelevant targets where both spatiotemporal control in a cellular setting and a reporting mechanism would be beneficial. An all-photonic method is described, in which (i) the release of an active kinase inhibitor is controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the inhibitor to its corresponding target.
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| 2. |
- Hussein, Brwa Ali, 1984, et al.
(författare)
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Impact of NK Cell Activating Receptor Gene Variants on Receptor Expression and Outcome of Immunotherapy in Acute Myeloid Leukemia
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer cells are important effector cells in the immune response against myeloid malignancies. Previous studies show that the expression of activating NK cell receptors is pivotal for efficient recognition of blasts from patients with acute myeloid leukemia (AML) and that high expression levels impact favorably on patient survival. This study investigated the potential impact of activating receptor gene variants on NK cell receptor expression and survival in a cohort of AML patients receiving relapse-preventive immunotherapy with histamine dihydrochloride and low-dose IL-2 (HDC/IL-2). Patients harboring the G allele of rs1049174 in the KLRK1 gene encoding NKG2D showed high expression of NKG2D by CD56(bright) NK cells and a favorable clinical outcome in terms of overall survival. For DNAM-1, high therapy-induced receptor expression entailed improved survival, while patients with high DNAM-1 expression before immunotherapy associated with unfavorable clinical outcome. The previously reported SNPs in NCR3 encoding NKp30, which purportedly influence mRNA splicing into isoforms with discrete functions, did not affect outcome in this study. Our results imply that variations in genes encoding activating NK cell receptors determine receptor expression and clinical outcome in AML immunotherapy.
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| 3. |
- Johnsson, Åse (Allansdotter), 1966, et al.
(författare)
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Extracolonic Findings-Identification at Low-Dose CTC.
- 2021
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Ingår i: Radiation protection dosimetry. - : Oxford University Press (OUP). - 1742-3406 .- 0144-8420. ; 195:3-4, s. 188-197
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Tidskriftsartikel (refereegranskat)abstract
- In contrast to optical colonoscopy, computed tomography colonography (CTC) has the ability to reveal pathology outside of the colon. While identification of colorectal lesions at CTC requires only limited radiation dose, the detection of abnormalities in extracolonic soft tissue requires more radiation. The purpose of this study was to investigate the influence of ultra-low-dose (ULD) CTC on the detection and characterisation of extracolonic findings. In a prospective study 49 patients with colorectal symptoms were examined with CTC adding a ULD series (mean effective dose 0.9±0.4mSv) to the normal unenhanced standard dose (SD) series (mean effective dose 3.6±1.2mSv). Five radiologists individually and blindly evaluated the ULD, followed by evaluation of the SD after ≥9weeks (median 35weeks). A ViewDEX-based examination protocol was used, including a confidence scale and a graded assessment of need for follow-up according to the CTC Reporting and Data System (C-RADS E0-E4). The reference findings comprised the combined information from CTC (ULD, SD and contrast-enhanced CTC series) and a 4-year radiological and clinical follow-up. For the overall detection of reference findings (E2-E4) we found a statistically significant difference in favour of SD. This, however, was not the case when looking at classification of possibly important/important reference findings (E3-E4). Our results suggest that CTC with ULD (0.9mSv) is comparable to SD (3.6mSv) for identification of clinically relevant extracolonic pathology, but there is a large inter-observer variability.
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| 4. |
- Komic, Hana, et al.
(författare)
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HLA-B*44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia
- 2023
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Ingår i: Cancer Immunology Immunotherapy. - 0340-7004. ; 72, s. 3559-3566
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Tidskriftsartikel (refereegranskat)abstract
- HLA-B alleles are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. The encoded HLA-B proteins are pivotal in antigen presentation to cytotoxic T cells, and some variants containing a Bw4 motif also serve as ligands to the killer immunoglobulin-like receptors (KIR) 3DL1/S1 of NK cells. We investigated the potential impact of HLA-B genotypes on the efficacy of immunotherapy for relapse prevention in acute myeloid leukemia (AML). Seventy-eight non-transplanted AML patients receiving HDC/IL-2 in the post-consolidation phase were genotyped for HLA-B and KIR genes. HLA-B*44 heralded impaired LFS (leukemia-free survival) and overall survival (OS), but the negative association with outcome was not shared across alleles of the HLA-B44 supertype. Notably, HLA-B*44 is one of few HLA-B44 supertype alleles containing a Bw4 motif with a threonine at position 80, which typically results in weak binding to the inhibitory NK receptor, KIR3DL1. Accordingly, a strong interaction between KIR3DL1 and Bw4 was associated with superior LFS and OS (p = 0.014 and p = 0.027, respectively). KIR3DL1(+) NK cells from 80 T-Bw4 donors showed significantly lower degranulation responses and cytokine responses than NK cells from 80I-Bw4 donors, suggesting impaired KIR3DL1-mediated education in 80 T-Bw4 subjects. We propose that presence of a strong KIR3DL1(+)-Bw4 interaction improves NK cell education and thus is advantageous in AML patients receiving HDC/IL-2 immunotherapy for relapse prevention.
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| 5. |
- Thoren, Fredrik, 1959, et al.
(författare)
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CT colonography: implementation, indications, and technical performance - a follow-up national survey.
- 2019
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Ingår i: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 60:3, s. 271-277
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Tidskriftsartikel (refereegranskat)abstract
- Background Computed tomography colonography (CTC) is an accepted complement or alternative to optical colonoscopy (OC) but its implementation is incompletely analyzed, and technical performance varies between centers. Purpose To evaluate implementation, indications, and technical performance of CTC in Sweden and to evaluate compliance to international guidelines. Material and Methods A structured, self-assessed questionnaire regarding implementation and technical performance of CTC was sent to all eligible radiology departments in Sweden. Eighty-six out of 89 departments replied. Comparisons were made with similar national surveys from 2004 and 2009. Results The number of centers performing CTC gradually increased from 23 in 2004 to 77 in 2016. In parallel, centers performing barium enema (BE) examinations have decreased from 89 in 2004 to 13 in 2016. Main reasons stated for still performing BE were lack of resources regarding CTC/OC. Main reasons for not performing CTC were lack of suitable software, lack of machine/reading time, and lack of experience. The majority of centers follow international CTC guidelines. An important exception is fecal tagging, which was implemented in only 63% of the centers. Incomplete OC remains a major indication for CTC, while preoperative CTC in colorectal cancer and follow-up after diverticulitis have emerged as new indications. Conclusion CTC today is well implemented in routine healthcare but still lacking in capacity. Indications have expanded over time, and most departments perform "state of the art" CTC, although fecal tagging is incompletely implemented.
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