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- Stratmann, Svea, 1989-, et al.
(författare)
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Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children
- 2023
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 37:3, s. 550-559
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Tidskriftsartikel (refereegranskat)abstract
- Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
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| 2. |
- Elsaid, K., et al.
(författare)
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Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia
- 2023
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:5, s. 794-805
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Tidskriftsartikel (refereegranskat)abstract
- Objective In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1 beta (IL-1 beta)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband).Methods We conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1 beta-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout.Results Lubricin level was attenuated in human proband serum and associated with elevated acute-phase reactants and inflammatory whole-blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter-alpha trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P < 0.01). Lubricin blunted urate crystal precipitation and IL-1 beta induction of xanthine oxidase and urate in cultured macrophages (P < 0.001). In lubricin-deficient mice, injection of IL-1 beta in knees increased xanthine oxidase-positive synovial resident M1 macrophages (P < 0.05).Conclusion Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization and blunted IL-1 beta-induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR-2 signaling.
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| 4. |
- Mattebo, Magdalena, Docent, 1976-, et al.
(författare)
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Guideline documents on caesarean section on maternal request in Sweden : varying usability with a restrictive approach
- 2023
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Ingår i: BMC Health Services Research. - : BioMed Central (BMC). - 1472-6963. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGlobally, studies illustrate different approaches among health care professionals to decision making about caesarean section (CS) and that attitudes regarding the extent to which a CS on maternal request (CSMR) can be granted vary significantly, both between professionals and countries. Absence of proper regulatory frameworks is one potential explanation for high CSMR rates in some countries, but overall, it is unclear how recommendations and guidelines on CSMR relate to CSMR rates. In Sweden, CSMR rates are low by international comparison, but statistics show that the extent to which maternity clinics perform CSMR vary among Sweden’s 21 self-governing regions. These regions are responsible for funding and delivery of healthcare, while national guidelines provide guidance for the professions throughout the country; however, they are not mandatory. To further understand considerations for CSMR requests and existing practice variations, the aim was to analyse guideline documents on CSMR at all local maternity clinics in Sweden.MethodsAll 43 maternity clinics in Sweden were contacted and asked for any guideline documents regarding CSMR. All clinics replied, enabling a total investigation. We used a combined deductive and inductive design, using the framework method for the analysis of qualitative data in multi-disciplinary health research.ResultsOverall, 32 maternity clinics reported guideline documents and 11 denied having any. Among those reporting no guideline documents, one referred to using national guideline document. Based on the Framework method, four theme categories were identified: CSMR is treated as a matter of fear of birth (FOB); How important factors are weighted in the decision-making is unclear; Birth contracts are offered in some regions; and The post-partum care is related to FOB rather than CSMR.ConclusionIn order to offer women who request CS equal and just care, there is a pressing need to either implement current national guideline document at all maternity clinics or rewrite the guideline documents to enable clinics to adopt a structured approach. The emphasis must be placed on exploring the reasons behind the request and providing unbiased information and support. Our results contribute to the ongoing discussion about CSMR and lay a foundation for further research in which professionals, as well as stakeholders and both women planning pregnancy and pregnant women, can give their views on this issue.
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