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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Denk, Stephanie, et al.
(författare)
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Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects
- 2017
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 198:12, s. 4846-4854
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Tidskriftsartikel (refereegranskat)abstract
- During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.
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| 3. |
- Fritz, Josef, et al.
(författare)
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The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers
- 2020
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 49:1, s. 193-204
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified.METHODS: Altogether 510 471 individuals from six European cohorts, with a mean age of 43.1 years, were included. We used the triglyceride glucose product (TyG index) as a surrogate measure for insulin resistance. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with 10 common obesity-related cancers, and quantified the proportion of the effect of BMI mediated through TyG index on the log-transformed hazard ratio (HR) scale.RESULTS: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney HR per one standard deviation increase 1.13, 95% confidence interval: 1.07 to 1.20], liver (1.13, 1.04 to 1.23), pancreas (1.12, 1.06 to 1.19), colon (1.07, 1.03 to 1.10) and rectum (1.09, 1.04 to 1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%) and colon (20%); smaller proportions for kidney (15%) and liver (11%). Little or no mediation was observed for breast (postmenopausal), endometrial and ovarian cancer. Results were similar for males and females, except for pancreatic cancer where the proportions mediated were 20% and 91%, respectively.CONCLUSIONS: The TyG index was associated with increased risk of cancers of the digestive system and substantially mediated the effect of BMI, suggesting that insulin resistance plays a promoting role in the pathogenesis of gastrointestinal cancers.
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| 5. |
- Hemels, Sigrid, et al.
(författare)
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Chapter 24, The Netherlands
- 2018
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Ingår i: Improving tax compliance in a globalized world. - 2451-8360. - 9789087224523 - 9789087224530 - 9789087224547 ; 9, s. 577-599
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This chapter discusses the tax gap in the Netherlands, access to information needed by the Dutch tax administration, exchange of information between the tax administration of the Netherlands and of other countries, cooperation between the Dutch tax administration and other Dutch law enforcement agencies, cooperative compliance and risk management in the Netherlands, the way the collection of taxes is improved in the Netherlands, the advantages for tax payers and challenges ahead.
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| 6. |
- Hemels, Sigrid, et al.
(författare)
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Netherlands
- 2019
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Ingår i: Implementing Key BEPS Actions: Where Do We Stand?. - 9789087225650 ; 12, s. 593-618
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This is the Dutch contribution to the book Implementing Key BEPS Actions: Where Do We Stand? Discussed are amongst others measures against hybrid mismatch arrangements, CFC rules, interest deductions, countering harmful tax practices, transfer pricing and the MLI.
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| 7. |
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| 8. |
- Henkow, Oskar, et al.
(författare)
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Taxable persons
- 2014
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Ingår i: ECJ - Recent Developments in Value Added Tax. - 9783707327533 ; , s. 69-88
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Bokkapitel (refereegranskat)
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