| 1. |
- Dyczynski, M, et al.
(författare)
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Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment
- 2018
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:9, s. 846-
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GCs) are metabolic hormones with immunosuppressive effects that have proven effective drugs against childhood acute lymphoblastic leukemia (ALL). Yet, the role of metabolic reprogramming in GC-induced ALL cell death is poorly understood. GCs efficiently block glucose uptake and metabolism in ALL cells, but this does not fully explain the observed induction of autophagy and cell death. Here, we have performed parallel time-course proteomics, metabolomics, and isotope-tracing studies to examine in detail the metabolic effects of GCs on ALL cells. We observed metabolic events associated with growth arrest, autophagy, and catabolism prior to onset of apoptosis: nucleotide de novo synthesis was reduced, while certain nucleobases accumulated; polyamine synthesis was inhibited; and phosphatidylcholine synthesis was induced. GCs suppressed not only glycolysis but also entry of both glucose and glutamine into the TCA cycle. In contrast, expression of glutamine-ammonia ligase (GLUL) and cellular glutamine content was robustly increased by GC treatment, suggesting induction of glutamine synthesis, similar to nutrient-starved muscle. Modulating medium glutamine and dimethyl-α-ketoglutarate (dm-αkg) to favor glutamine synthesis reduced autophagosome content of ALL cells, and dm-αkg also rescued cell viability. These data suggest that glutamine synthesis affects autophagy and possibly onset of cell death in response to GCs, which should be further explored to understand mechanism of action and possible sources of resistance.
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| 2. |
- Jung, Christian, et al.
(författare)
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A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
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Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
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| 3. |
- Kolosenko, Iryna, et al.
(författare)
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Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:4, s. E51-E61
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon-(IFN)-stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock-down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor-9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors. What's new? Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.
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| 4. |
- Nilsonne, G., et al.
(författare)
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Increased global FMRI signal variability after partial sleep deprivation : Findings from the Stockholm sleepy brain study
- 2017
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Ingår i: SLEEP. - : Oxford University Press (OUP). - 0161-8105 .- 1550-9109. ; 40, s. A40-A40
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Konferensbidrag (refereegranskat)abstract
- Introduction: Neural correlates of sleep deprivation are not fully understood and the difference between young and older adults in this regard has received little attention. We aimed to investigate the effect of partial sleep deprivation on resting state connectivity.Methods: 30 younger (20–30 years) and 23 older (65–75 years) healthy participants underwent MR imaging after normal sleep and partial sleep deprivation (3 h sleep). We acquired two runs of eyes-open resting state functional magnetic resonance images. Participants were monitored with eye-tracking to ensure their eyes remained open during scanning.Results: Global signal variability, defined as log-transformed standard deviation of average gray matter signal, was increased following partial sleep deprivation (0.16 [0.07, 0.24], p = 0.0004). In contrast to previous studies, we did not find that partial sleep deprivation inhibited connectivity in the default mode network, nor in other major networks investigated.Conclusion: Sleep deprivation caused increased global signal variability. This novel finding should be confirmed using independent data. Our finding of no difference in default mode connectivity in the sleep deprived state, could possibly be due to stricter monitoring of participants’ wakefulness compared to some earlier studies.
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| 5. |
- Pijuan-Galito, Sara, et al.
(författare)
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Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reliable, scalable and time-efficient culture methods are required to fully realize the clinical and industrial applications of human pluripotent stem (hPS) cells. Here we present a completely defined, xeno-free medium that supports long-term propagation of hPS cells on uncoated tissue culture plastic. The medium consists of the Essential 8 (E8) formulation supplemented with inter-alpha-inhibitor (I alpha I), a human serum-derived protein, recently demonstrated to activate key pluripotency pathways in mouse PS cells. IaI efficiently induces attachment and long-term growth of both embryonic and induced hPS cell lines when added as a soluble protein to the medium at seeding. IaI supplementation efficiently supports adaptation of feeder-dependent hPS cells to xeno-free conditions, clonal growth as well as single-cell survival in the absence of Rho-associated kinase inhibitor (ROCKi). This time-efficient and simplified culture method paves the way for large-scale, high-throughput hPS cell culture, and will be valuable for both basic research and commercial applications.
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| 6. |
- Stoller, R. E., et al.
(författare)
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Impact of Short-Range Forces on Defect Production from High Energy Collisions
- 2016
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 12:6, s. 2871-2879
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Tidskriftsartikel (refereegranskat)abstract
- Primary radiation damage formation in solid materials typically involves collisions between atoms that have up to a few hundred keV of kinetic energy. Dining these collisions, the-distance between two colliding atoms can approach 0.05 nm. At such small atomic separations, force fields fitted-to equilibrium properties tend to significantly underestimate the potential-energy-of the colliding dieter. To enable molecular dynamics simulations of high-energy collisions, it is common practice to use a screened Coulomb, force field to describe the interactions and to smoothly join this to the equilibrium force field at a suitable interatomic spacing. However, there is,no accepted standard method for choosing the parameters used in the joining process, and our results prove that defect production is sensitive to how the force field's are linked. A new procedure is presented that involves the use of ab initio calculations to,determine the magnitude and spatial dependence of the pair interactions at intermediate distances, along with systematic criteria for choosing the joining parameters. Results are presented for the case of nickel, which demonstrate the use and validity of the procedure.
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