| 1. |
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| 2. |
- Forte, A, et al.
(författare)
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c-Myc antisense oligonucleotides preserve smooth muscle differentiation and reduce negative remodelling following rat carotid arteriotomy
- 2005
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Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 42:3, s. 214-225
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The vascular biology of restenosis is complex and not fully understood, thus explaining the lack of effective therapy for its prevention in clinical settings. The role of c-Myc in arteriotomy-induced stenosis, smooth muscle cell (SMC) differentiation and apoptosis was investigated in rat carotids applying full phosphorothioate antisense ( AS) oligonucleotides (ODNs). Methods: Carotid arteries from WKY rats were submitted to arteriotomy and to local application of ODNs through pluronic gel. Apoptosis ( deoxynucleotidyl transferase-mediated dUTP nick end-labelling), SMC differentiation (SM22 immunofluorescence) and vessel morphology and morphometry ( image analysis) were determined 2, 5 and 30 days after injury, respectively. Results: AS ODNs induced a 60% decrease of target c-Myc mRNA 4 h after surgery in comparison to control sense ( S) and scrambled ODN-treated carotids (p < 0.05). A significant 37 and 50% decrease in SM22 protein in the media of S ODN-treated and untreated carotids was detected when compared to uninjured contralateral arteries (p < 0.05). This reduction in SM22 expression was prevented in AS ODN-treated carotids. Stenosis was mainly due to adventitial constrictive remodelling. Lumen area in AS ODN-treated carotids was 35% greater than in control arteries 30 days after surgery (p < 0.05). TUNEL assay revealed increased apoptosis in AS ODN-treated carotids (p < 0.05). Conclusions: c-Myc AS ODNs reduce arteriotomy-induced negative remodelling. This is accompanied by maintained SMC differentiation and greater apoptosis. The combination of reduced c-Myc-induced proliferation and increased apoptosis may thus underlie the less severe remodelling upon treatment with c-Myc mRNA AS ODN.
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| 3. |
- Kumar, B, et al.
(författare)
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Upregulated TRPC1 Channel in Vascular Injury In Vivo and Its Role in Human Neointimal Hyperplasia.
- 2006
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Ingår i: Circulation Research. - 0009-7330. ; 98:4, s. 557-563
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Tidskriftsartikel (refereegranskat)abstract
- Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Alsiö, Åsa, 1965, et al.
(författare)
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Early quantification of HCV core antigen may help to determine the duration of therapy for chronic genotype 2 or 3 HCV infection
- 2012
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Ingår i: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 0934-9723 .- 1435-4373. ; 31:7, s. 1631-1635
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the utility of hepatitis C virus (HCV) core antigen (coreAg) assessment for the identification of candidates for short-term therapy. Plasma samples from HCV genotype 2 or 3-infected patients participating in the NORDynamIC trial (n = 382) comparing 12 and 24 weeks of combination treatment with pegylated interferon-alpha 2a and a fixed dose of 800 mg ribavirin daily were analyzed for coreAg. Among the 126 patients (33% of the intention-to-treat population) achieving HCV coreAg levels in plasma below 0.2 pg/mL when assayed on treatment day 3, sustained viral response (SVR) rates of 86% and 84% were achieved in the 12- and 24-week arms, respectively. Similarly, among patients having received at least 80% of the target dose of both pegylated interferon alpha-2a and of ribavirin for at least 80% of the target treatment duration (per-protocol analysis), the SVR rates were 89% and 95%, respectively. Twelve weeks of combination treatment may be sufficient for genotype 2 or 3-infected patients achieving HCV coreAg levels below 0.2 pg/mL by day 3, signaling a rapid clearance of HCV viremia.
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| 8. |
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| 9. |
- Cohen, Samuel I. A., et al.
(författare)
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Proliferation of amyloid-beta 42 aggregates occurs through a secondary nucleation mechanism
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:24, s. 9758-9763
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Tidskriftsartikel (refereegranskat)abstract
- The generation of toxic oligomers during the aggregation of the amyloid-beta (A beta) peptide A beta 42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer's disease, but the molecular pathways that control pathological aggregation have proved challenging to identify. Here, we use a combination of kinetic studies, selective radiolabeling experiments, and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. Our results show that once a small but critical concentration of amyloid fibrils has accumulated, the toxic oligomeric species are predominantly formed from monomeric peptide molecules through a fibril-catalyzed secondary nucleation reaction, rather than through a classical mechanism of homogeneous primary nucleation. This catalytic mechanism couples together the growth of insoluble amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer's disease. These results reveal that the aggregation of A beta 42 is promoted by a positive feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. Our findings bring together the main molecular species implicated in the A beta aggregation cascade and suggest that perturbation of the secondary nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic A beta 42 oligomers.
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| 10. |
- Eussen, Simone R. B. M., et al.
(författare)
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Simultaneous intake of oat bran and atorvastatin reduces their efficacy to lower lipid levels and atherosclerosis in LDLr-/- mice
- 2011
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 64:1, s. 36-43
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Tidskriftsartikel (refereegranskat)abstract
- The present study aimed to investigate the effects of separate and simultaneous dietary intake of atorvastatin (ATO) and the soluble fiber oat bran on serum and hepatic lipid levels and the degree of atherosclerosis. Ninety female LDL-receptor-deficient (LDLr-/-) mice were fed a Western-type diet containing either low dose (0.0025%), high dose (0.01%) or no ATO, with or without oat bran (27%) (n = 15 per group) for 16 weeks. Both ATO and oat bran were effective in reducing serum total cholesterol levels (low ATO: -5.48, high ATO: -9.12, oat bran: -3.82 mmol/l, compared to control (no ATO/no oat bran), all p < 0.0001). When oat bran was added to a low dose ATO, the cholesterol-lowering effects of this combination were 50% smaller compared to the low dose ATO diet alone (between-group difference: 2.77 mmol/l, p = 0.002), whereas total cholesterol decreased to a similar extent in the groups fed a high dose ATO, with or without oat bran (between-group difference: 1.10 mmol/l, p = 0.21). Serum LDL- and HDL-cholesterol, triglycerides, hepatic lipid levels and atherosclerotic lesion development showed a similar pattern. In conclusion, the efficacy of oat bran and atorvastatin to lower lipid levels and atherosclerosis is reduced after simultaneous intake. We hypothesize that oat bran inhibits the intestinal absorption of atorvastatin, and consequently its cholesterol-lowering effects. The effects are likely dependent on the type of statin and dietary fiber, and on the relative timing of intake of the statin and the dietary fiber. Future studies should focus on these aspects to provide further insight into the exact mechanism of this food-drug interaction. (C) 2011 Elsevier Ltd. All rights reserved.
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| 11. |
- Lagging, Martin, 1965, et al.
(författare)
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Retreatment with peg-interferon and ribavirin in patients with chronic hepatitis C virus genotype 2 or 3 infection with prior relapse
- 2013
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 48:7, s. 839-847
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. Uncertainty remains regarding the efficacy of retreatment with current standard-of-care peg-interferon (peg-IFN) and ribavirin among patients infected with hepatitis C virus (HCV) genotypes 2 or 3 with relapse after prior therapy. Materials and methods. Seventy-one patients with chronic HCV genotype 2/3 with prior relapse were enrolled in a phase III multicenter study. Patients were retreated with peg-IFN alpha-2a 180 mu g per week and ribavirin 1000/1200 mg daily. Patients having received previous therapy for 24 weeks were retreated for 48 weeks (Group A), whereas patients having received at least 12 weeks but less than 24 weeks of treatment were allocated to either 48 (Group B) or 24 weeks (Group C) on the basis of whether they had achieved rapid virological response (RVR). Results. Sustained virological response (SVR) rates of 53%, 81% and 75% were achieved in groups A, B and C, respectively. Patients with favorable baseline characteristics, e. g., less advanced liver fibrosis, age < 40 years, duration of infection < 20 years, or BMI < 25 kg/m(2), tended to have more favorable outcomes. All patients achieving HCV RNA below 1000 IU/mL day 6 achieved SVR in contrast to none of the patients with detectable HCV RNA at week 12. Conclusions. Retreatment with peg-IFN and ribavirin for 24-48 weeks entails SVR among the majority of HCV genotype 2/3 infected patients with prior relapse. However, in light of the prolonged treatment duration, moderate effect and considerable side effects, deterring therapy until new options are available may be preferential, particularly in patients previously treated for 24 weeks.
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| 12. |
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| 13. |
- Lindh, Magnus, 1960, et al.
(författare)
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Interleukin 28B Gene Variation at rs12979860 Determines Early Viral Kinetics During Treatment in Patients Carrying Genotypes 2 or 3 of Hepatitis C Virus
- 2011
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 203:12, s. 1748-1752
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Tidskriftsartikel (refereegranskat)abstract
- Single-nucleotide polymorphisms upstream of the interleukin 28B (interferon lambda 3) gene (IL28B) strongly influence treatment efficacy in patients carrying hepatitis C virus (HCV) of genotype 1. In patients receiving 12 or 24 weeks of interferon-ribavirin therapy for infection with genotype 2 or 3 (n = 341), we found that rs12979860 strikingly determined the first phase of viral elimination (P < .001). In patients treated for 24 weeks, rs12979860 also predicted the rate of sustained virologic response (P = .02), especially among those with high baseline HCV RNA levels (P = .002) or older than 45 years (P = .01). Patients carrying CCrs12979860 had higher baseline HCV RNA levels (P < .001) and did not, when treated for 12 weeks, achieve sustained virologic response more often than those carrying CTrs1297986 or TTrs1297986. The results indicate that IL28B gene testing may identify patients carrying genotype 2 or 3 who could benefit from extended treatment.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Sparrow, M P, et al.
(författare)
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Isoforms of myosin in smooth muscle
- 1987
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Ingår i: Progress in Clinical and Biological Research. - 0361-7742. ; 245, s. 67-79
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Tidskriftsartikel (refereegranskat)
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| 19. |
- Swärd, Karl, et al.
(författare)
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Inhibition of Rho-associated kinase blocks agonist-induced Ca2+ sensitization of myosin phosphorylation and force in guinea-pig ileum
- 2000
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Ingår i: Journal of Physiology. - 1469-7793. ; 522, s. 33-49
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Tidskriftsartikel (refereegranskat)abstract
- Ca2+ sensitization of smooth muscle contraction involves the small GTPase RhoA, inhibition of myosin light chain phosphatase (MLCP) and enhanced myosin regulatory light chain (LC20) phosphorylation. A potential effector of RhoA is Rho-associated kinase (ROK). The role of ROK in Ca2+ sensitization was investigated in guinea-pig ileum. Contraction of permeabilized muscle strips induced by GTPgammaS at pCa 6.5 was inhibited by the kinase inhibitors Y-27632, HA1077 and H-7 with IC50 values that correlated with the known Ki values for inhibition of ROK. GTPgammaS also increased LC20 phosphorylation and this was prevented by HA1077. Contraction and LC20 phosphorylation elicited at pCa 5.75 were, however, unaffected by HA1077. Pre-treatment of intact tissue strips with HA1077 abolished the tonic component of carbachol-induced contraction and the sustained elevation of LC20 phosphorylation, but had no effect on the transient or sustained increase in [Ca2+]i induced by carbachol. LC20 phosphorylation and contraction dynamics suggest that the ROK-mediated increase in LC20 phosphorylation is due to MLCP inhibition, not myosin light chain kinase activation. In the absence of Ca2+, GTPgammaS stimulated 35S incorporation from [35S]ATPgammaS into the myosin targeting subunit of MLCP (MYPT). The enhanced thiophosphorylation was inhibited by HA1077. No thiophosphorylation of LC20 was detected. These results indicate that ROK mediates agonist-induced increases in myosin phosphorylation and force by inhibiting MLCP activity through phosphorylation of MYPT. Under Ca2+-free conditions, ROK does not appear to phosphorylate LC20 in situ, in contrast to its ability to phosphorylate myosin in vitro. In particular, ROK activation is essential for the tonic phase of agonist-induced contraction.
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| 20. |
- Söderholm, Jonas, 1978, et al.
(författare)
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Impact of Soluble CD26 on Treatment Outcome and Hepatitis C Virus-Specific T Cells in Chronic Hepatitis C Virus Genotype 1 Infection
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Background Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50–80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells. Methods Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8+ T cells. Results Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8+ T cells (P = 0.02). Conclusions Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8+ T cells.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Al-Dury, Samer, et al.
(författare)
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Impaired SARS-CoV-2-specific T-cell reactivity in patients with cirrhosis following mRNA COVID-19 vaccination
- 2022
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Ingår i: JHEP Reports. - : Elsevier BV. - 2589-5559. ; 4:7
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Cirrhosis entails elevated risk of COVID-19-associated mortality. This study determined T cell-mediated and antibody reactivity against the spike 1 (S1) protein of SARS-CoV-2 among 48 patients with cirrhosis and 39 healthy controls after mRNA COVID-19 vaccination. Methods: SARS-CoV-2-specific T-cell reactivity was measured by induced level of T cell-derived interferon-gamma (IFN-gamma) in blood cells stimulated ex vivo with multimeric peptides spanning the N-terminal portion of S1. S1-induced IFN-gamma was quantified before and after the 1st and 2nd vaccination (BNT162b2, Pfizer-BioNTech or mRNA-1273, Moderna) alongside serum IgG against the receptor-binding domain (RBD) within S1 (anti-RBD-S1 IgG). Results: T-cell reactivity against S1 was reduced in patients with cirrhosis after the 1st (p < 0.001 vs. controls) and 2nd (p < 0.001) vaccination. Sixty-eight percent of patients lacked detectable S1-specific T-cell reactivity after the 1st vaccination vs. 19% in controls (odds ratio 0.11, 95% CI 0.03-0.48, p = 0.003) and 36% remained devoid of reactivity after the 2nd vaccination vs. 6% in controls (odds ratio 0.12, 95% CI 0.03-0.59, p = 0.009). T-cell reactivity in cirrhosis remained significantly impaired after correction for potential confounders in multivariable analysis. Advanced cirrhosis (Child-Pugh class B) was associated with absent or lower T-cell responses (p < 0.05 vs. Child-Pugh class A). The deficiency of T-cell reactivity was paralleled by lower levels of anti-RBD-S1 IgG after the 1st (p < 0.001 vs. controls) and 2nd (p < 0.05) vaccination. Conclusions: Patients with cirrhosis show deficient T-cell reactivity against SARS-CoV-2 antigens along with diminished levels of anti-RBD-S1 IgG after dual COVID-19 vaccination, highlighting the need for vigilance and additional preventative measures. Clinical trial registration: EudraCT 2021-000349-42 Lay summary: T cells are a pivotal component in the defence against viruses. We show that patients with cirrhosis have impaired SARS-CoV-2-specific T-cell responses and lower antibody levels after mRNA vaccination against COVID-19 compared with healthy controls. Patients with more advanced liver disease exhibited particularly inferior vaccine responses. These results call for additional preventative measures in these patients. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).
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| 25. |
- Aurelius, Johan, 1980, et al.
(författare)
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NOX2-dependent immunosuppression in chronic myelomonocytic leukemia
- 2017
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Ingår i: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 102:2, s. 459-466
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8(+) T effector memory cells, and CD8(+) T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34(+)) in blood was associated with reduced expression of several NK cell-activating receptors. We propose that CMML cells may use extracellular ROS as a targetable mechanism of immune escape.
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| 26. |
- Berndtsson, M., et al.
(författare)
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Is circular economy a magic bullet?
- 2017
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Ingår i: Natural Resources Available Today and in the Future: How to Perform Change Management for Achieving a Sustainable World. - Cham : Springer International Publishing. - 9783319542638 - 9783319542614 ; , s. 281-295
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 27. |
- Brune, Mats, 1950, et al.
(författare)
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Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 108:1, s. 88-96
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Tidskriftsartikel (refereegranskat)abstract
- The primary objective of this phase 3 study was to determine whether postconsolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) improved the leukemia-free survival (LFS) of adult patients with acute myeloid leukemia (AML) in complete remission (CR). Three hundred twenty patients with AML (median age, 57 years; range, 18-84 years) were stratified by CR1 or subsequent CR (CR > 1) and randomly assigned to treatment with HDC/IL-2 or no treatment (control). Treatment comprised 10 21-day cycles with IL-2 (16 400 U/kg) plus HDC (0.5 mg); both compounds were administered by subcutaneous injection twice daily. Study arms were balanced for age, sex, previous treatment, leukemic karyotypes, time from CR to inclusion, and frequency of secondary leukemia. Three years after enrollment of the last patient, treatment with HDC/IL-2 was found to improve LFS over control in the study population (CR1 + CR > 1, n = 320; P < .01, log-rank test). For patients in CR1 (n = 261), treatment significantly improved LFS (P = .01) with 3-year LFS estimates of 40% (HDC/IL-2) compared with 26% (control). Side effects were typically mild to moderate. These results indicate that HDC/IL-2 treatment offers an efficacious and tolerable treatment for patients with AML in remission.
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| 28. |
- Brunkwall, Louise, et al.
(författare)
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The Malmö Offspring Study (MOS) : design, methods and first results.
- 2021
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Ingår i: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 36, s. 103-116
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Tidskriftsartikel (refereegranskat)abstract
- As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18-71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms.
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| 29. |
- Buyse, M, et al.
(författare)
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Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission
- 2011
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Ingår i: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL. - : Ferrata Storti Foundation (Haematologica). - 0390-6078. ; 96:8, s. 1106-1112
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia. DESIGN AND METHODS: Data were analyzed from a randomized Phase III trial of remission maintenance immunotherapy with histamine dihydrochloride plus low-dose interleukin-2 versus no treatment in adults with acute myeloid leukemia. A two-stage surrogate validation model was applied in which correlations between Kaplan-Meier estimates of leukemia-free survival and overall survival, and between log hazard ratios reflecting treatment effects were analyzed. Country of patient enrollment was the unit of analysis. RESULTS: Kaplan-Meier estimates of overall survival at 36, 48, and 60 months and leukemia-free survival at 24 months were reasonably correlated (R(2) ranging from 0.44 to 0.84) both for the overall (n=320) and first complete remission (n=261) populations. The effects of histamine dihydrochloride/interleukin-2 on log hazard ratios for leukemia-free survival and overall survival were well correlated (R(2)=0.88-0.93). CONCLUSIONS: The significant correlations between overall survival and the surrogate end point (leukemia-free survival) and between the effect of histamine dihydrochloride/interleukin-2 on leukemia-free survival and overall survival satisfy the two-stage surrogate validation model.
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| 30. |
- Di Russo, Jacopo, et al.
(författare)
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Endothelial basement membrane laminin 511 is essential for shear stress response
- 2017
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Ingår i: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 36:2, s. 183-201
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Tidskriftsartikel (refereegranskat)abstract
- Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM-1 and VE-cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1-positive/vinculin-positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin-mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE-cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.
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| 31. |
- Ericson, Ulrika, et al.
(författare)
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A Health-Conscious Food Pattern Is Associated with Prediabetes and Gut Microbiota in the Malmö Offspring Study
- 2020
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Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166. ; 150:4, s. 861-872
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diet is a determinant of gut microbiota. Both diet and gut microbiota have been linked to metabolic diseases. Objective: We aimed to examine data-driven food patterns in relation to the prevalence of prediabetes and gut microbiota composition and food pattern-associated bacteria in relation to prediabetes. Methods: Food patterns were extracted using principal component analysis in 1726 individuals (aged 18-71 y, 55% women, mean BMI = 25.5 kg/m2) without diabetes from the population-based Malmö Offspring Study. The gut (fecal) microbiota was analyzed by sequencing the 16S ribosomal RNA gene (V1-V3 region). Prediabetes classification was based on fasting glucose ≥6.0 mmol/L and/or glycated hemoglobin ≥42 mmol/L at baseline and/or type 2 diabetes diagnosis during follow-up (0-3.8 y). Logistic regression was used to investigate cross-sectional associations with prediabetes, and the general linear model to examine associations between food patterns and bacterial genera. Results: Two food patterns, the Health-conscious and the Sugar and High-Fat Dairy patterns, were identified. Adherence to the Health-conscious pattern was associated with a lower prevalence of prediabetes (OR comparing highest quintile with lowest: 0.54; 95% CI: 0.32, 0.92; P-trend = 0.03) and with the abundance of several gut bacterial genera, of which the most robust findings were with a higher abundance of Roseburia and Lachnospira and with a lower abundance of Eubacterium. Roseburia was also associated with a lower prevalence of prediabetes (OR comparing highest quintile with lowest: 0.56; 95% CI: 0.35, 0.92; P-trend = 0.01) and the association between the Health-conscious pattern and prediabetes was attenuated after adjustment for abundance of Roseburia and BMI. Adherence to the Sugar and High-Fat Dairy pattern was associated with a higher prevalence of prediabetes in women (P-trend across food pattern quintiles = 0.03). Conclusions: In this Swedish population-based study, a Health-conscious food pattern showed an inverse association with the prevalence of prediabetes. Potential underlying explanations may involve links between healthy diet and BMI, as well as gut microbiota, especially a higher abundance of Roseburia.
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| 32. |
- Ericson, Ulrika, et al.
(författare)
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Food patterns in relation to weight change and incidence of type 2 diabetes, coronary events and stroke in the Malmö Diet and Cancer cohort
- 2019
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Ingår i: European Journal of Nutrition. - : Springer Science and Business Media LLC. - 1436-6207 .- 1436-6215. ; 58:5, s. 1801-1814
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We examined if data-driven food-patterns associate with weight change, incidence of type 2 diabetes (T2D), coronary events (CE) and stroke. Methods: The study included 20,487 individuals (61% women) from the Malmö Diet and Cancer cohort, 45–74 years, without diabetes and CVD at baseline (1991–1996) and who did not report dietary changes. Diet was measured with a modified diet history method. During 15 years follow-up, 2206 T2D, 1571 CE and 1332 stroke cases were identified. Data on weight change after 16.7 years were available in 2627 individuals. Results: From principal component analysis, we identified six food-patterns which were similar in women and men. The first pattern, explaining 7% of the variance, was characterized by high intake of fibre-rich bread, breakfast cereals, fruits, vegetables, fish and low-fat yoghurt, and by low intake of low-fibre bread. This health conscious pattern was associated with lower T2D risk (HR comparing highest quintile with lowest: 0.75; 95% CI 0.61–0.92, 0.82; 95% CI 0.68–1.00 in women and men, respectively, P trends = 0.003, 0.01) and CE (HR 0.77; 95% CI 0.58–1.02, HR 0.83; 95% CI 0.68–1.01, P trends = 0.05, 0.07), and in men also with lower risk of ischemic stroke (HR 0.69; 95% CI 0.54–0.88; P trend = 0.001) and less pronounced weight gain (0.93 kg/10 years, P trend = 0.03). A low-fat product pattern was associated with increased T2D risk in gender combined analyses (P trend = 0.03) and a pattern characterized by dressing and vegetables with lower CE risk in men (P trend = 0.02). Conclusions: Our main finding was that a dietary pattern indicating health conscious food choices was associated with lower risk of cardiometabolic diseases in both genders.
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| 33. |
- Eriksson, Harald, 1977-, et al.
(författare)
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A suggested new bacteriophage genus, “Kp34likevirus”, within the Autographivirinae subfamily of Podoviridae
- 2015
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 7:4, s. 1804-1822
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Tidskriftsartikel (refereegranskat)abstract
- Klebsiella pneumoniae phages vB_KpnP_SU503 (SU503) and vB_KpnP_SU552A (SU552A) are virulent viruses belonging to theAutographivirinae subfamily of Podoviridae that infect and kill multi-resistant K. pneumoniae isolates. Phages SU503 and SU552A show high pairwise nucleotide identity to Klebsiella phages KP34 (NC_013649), F19 (NC_023567) and NTUH-K2044-K1-1 (NC_025418). Bioinformatic analysis of these phage genomes show high conservation of gene arrangement and gene content, conserved catalytically active residues of their RNA polymerase, a common and specific lysis cassette, and form a joint cluster in phylogenetic analysis of their conserved genes. Also, we have performed biological characterization of the burst size, latent period, host specificity (together with KP34 and NTUH-K2044-K1-1), morphology, and structural genes as well as sensitivity testing to various conditions. Based on the analyses of these phages, the creation of a new phage genus is suggested within the Autographivirinae, called “Kp34likevirus” after their type phage, KP34. This genus should encompass the recently genome sequenced Klebsiella phages KP34, SU503, SU552A, F19 and NTUH-K2044-K1-1.
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| 34. |
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| 35. |
- Grossi, Mario, et al.
(författare)
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Pyk2 inhibition promotes contractile differentiation in arterial smooth muscle
- 2017
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541. ; 232:11, s. 3088-3102
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Tidskriftsartikel (refereegranskat)abstract
- Modulation from contractile to synthetic phenotype of vascular smooth muscle cells is a central process in disorders involving compromised integrity of the vascular wall. Phenotype modulation has been shown to include transition from voltage-dependent toward voltage-independent regulation of the intracellular calcium level, and inhibition of non-voltage dependent calcium influx contributes to maintenance of the contractile phenotype. One possible mediator of calcium-dependent signaling is the FAK-family non-receptor protein kinase Pyk2, which is activated by a number of stimuli in a calcium-dependent manner. We used the Pyk2 inhibitor PF-4594755 and Pyk2 siRNA to investigate the role of Pyk2 in phenotype modulation in rat carotid artery smooth muscle cells and in cultured intact arteries. Pyk2 inhibition promoted the expression of smooth muscle markers at the mRNA and protein levels under stimulation by FBS or PDGF-BB and counteracted phenotype shift in cultured intact carotid arteries and balloon injury ex vivo. During long-term (24–96 hr) treatment with PF-4594755, smooth muscle markers increased before cell proliferation was inhibited, correlating with decreased KLF4 expression and differing from effects of MEK inhibition. The Pyk2 inhibitor reduced Orai1 and preserved SERCA2a expression in carotid artery segments in organ culture, and eliminated the inhibitory effect of PDGF stimulation on L-type calcium channel and large-conductance calcium-activated potassium channel expression in carotid cells. Basal intracellular calcium level, calcium wave activity, and store-operated calcium influx were reduced after Pyk2 inhibition of growth-stimulated cells. Pyk2 inhibition may provide an interesting approach for preserving vascular smooth muscle differentiation under pathophysiological conditions.
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| 36. |
- Hellstrand, Erik, et al.
(författare)
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Amyloid beta-Protein Aggregation Produces Highly Reproducible Kinetic Data and Occurs by a Two-Phase Process
- 2010
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 1:1, s. 13-18
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Tidskriftsartikel (refereegranskat)abstract
- Protein aggregation can lead to major disturbances of cellular processes and is associated with several diseases. We report kinetic and equilibrium data by ThT fluorescence and enzyme-linked immunosorbent assay of sufficient quality and reproducibility to form a basis for mechanistic understanding of amyloid beta-peptide (A beta) fibril formation. Starting from monomeric peptide in a pure buffer system without cosolvents, we find that the kinetics of A beta aggregation vary strongly with peptide concentration in a highly predictable manner. The free A beta concentration in equilibrium with fibrils was found to vary with total peptide concentration in a manner expected for a two-phase system. The free versus total A beta concentration was linear up to ca. 0.2,mu M, after which free A beta decreased with total A beta toward an asymptotic value. Our results imply that A beta fibril formation arises from a sequence of events in a highly predictable manner.
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| 37. |
- Hellstrand, Kristoffer, 1956, et al.
(författare)
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Age-Related Efficacy of Immunotherapy with Histamine Dihydrochloride and Interleukin-2 for Relapse Prevention in Acute Myeloid Leukemia
- 2011
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Ingår i: Annals of Hematology. - : Springer Science and Business Media LLC. - 0939-5555 .- 1432-0584. ; 90:Suppl. 1
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Tidskriftsartikel (refereegranskat)abstract
- Recurrence of leukemia after the completion of induction and consolidation chemotherapy is a significant clinical concern in acute myeloid leukemia (AML). Apart from allogeneic bone marrow transplantation there is no consensus about effective relapse-protective therapy beyond the consolidation phase, and the standard of care for the majority of patients in complete remission (CR) hence is no treatment. Here we present updated results from a phase 3 trial (n=320) evaluating the prevention of relapse in AML patients receiving immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2). This trial was previously reported to meet the primary endpoint of improved leukemia-free survival (LFS) in the primary population of all randomized patients. Our results imply that treatment with HDC/IL-2 prevents relapse in patients 40–70 years old in first CR (p=0.008, leukemia-free survival (LFS), n=190, log rank test) with a more than 80% relative increase in the likelihood of LFS at 3 years. HDC/IL-2 was not significantly efficacious in young patients (<40 years old). Further studies are underway to define the impact of HDC/IL-2 on immune function and the putative efficacy of therapy in genetic subgroups of AML.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Hellstrand, Sophie, et al.
(författare)
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Dietary Data in the Malmö Offspring Study : Reproducibility, Method Comparison and Validation against Objective Biomarkers
- 2021
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Irregular dietary intakes impairs estimations from food records. Biomarkers and method combinations can be used to improve estimates. Our aim was to examine reproducibility from two assessment methods, compare them, and validate intakes against objective biomarkers. We used the Malmö Offspring Study (55% women, 18-71 y) with data from a 4-day food record (4DFR) and a short food frequency questionnaire (SFFQ) to compare (1) repeated intakes (n = 180), (2) intakes from 4DFR and SFFQ (n = 1601), and (3) intakes of fatty fish, fruits and vegetables, and citrus with plasma biomarkers (n = 1433) (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid [CMPF], β-carotene and proline betaine). We also combined 4DFR and SFFQ estimates using principal component analysis (PCA). Moderate correlations were seen between repeated intakes (4DFR median ρ = 0.41, SFFQ median ρ = 0.59) although lower for specific 4DFR-items, especially fatty/lean fish (ρ ≤ 0.08). Between-method correlations (median ρ = 0.33) were higher for intakes of overall food groups compared to specific foods. PCA scores for citrus (proline betaine ρ = 0.53) and fruits and vegetables (β-carotene: ρ = 0.39) showed the highest biomarker correlations, whereas fatty fish intake from the SFFQ per se showed the highest correlation with CMPF (ρ = 0.46). To conclude, the reproducibility of SFFQ data was superior to 4DFR data regarding irregularly consumed foods. Method combination could slightly improve fruit and vegetable estimates, whereas SFFQ data gave most valid fatty fish intake.
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| 42. |
- Himpens, B, et al.
(författare)
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Free cytosolic calcium during spontaneous contractions in smooth muscle of the guinea-pig mesotubarium
- 1990
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Ingår i: Pflügers Archiv. - 0031-6768. ; 417:4, s. 404-409
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Tidskriftsartikel (refereegranskat)abstract
- The free intracellular calcium ion concentration ([Ca2+]i) was measured simultaneously with isometric force in strips of guinea-pig mesotubarium using the Fura-2 technique. During the relaxed period (5-15 min) between spontaneous contractions [Ca2+]i continues to decrease after full mechanical relaxation to reach a minimal level of 86 +/- 8 nM (n = 9) just before the start of the next contraction. During the spontaneous contractions (5-15 min) [Ca2+]i reached a maximum of 211 +/- 19 nM and then oscillated between 155 +/- 16 nM and 194 +/- 9 nM. Increased extracellular Ca2+ concentration to 10 mM from the standard concentration of 1.5 mM caused a decreased frequency of spontaneous contractions and an increase in [Ca2+]i both in the relaxed and contracted states. In 10 mM extracellular Ca2+, addition of AlF4-, as 1 mM NaF + 10 microM AlCl3, caused a sustained increase in [Ca2+]i and maintained force. Addition of verapamil (10 microM) in this situation decreased [Ca2+]i to the resting level. The results suggest that the cyclic appearance of trains of action potentials is related to variation in [Ca2+]i, possibly via inactivation of Ca2(+)-dependent K+ channels.
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| 43. |
- Lydrup, M L, et al.
(författare)
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Effect of glibenclamide on membrane response to metabolic inhibition in smooth muscle of rat portal vein
- 1994
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Ingår i: Journal of Vascular Research. - 1423-0135. ; 31:2, s. 82-91
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Tidskriftsartikel (refereegranskat)abstract
- Vascular smooth muscle tone is dependent on oxidative metabolism, a phenomenon of potential importance for the metabolic regulation of blood flow to tissues. The response of the rat portal vein to inhibition of cell respiration by cyanide (0.1-1 mM) is a reduction of its spontaneous myogenic activity. The trains of action potentials triggering phasic contractions are reduced in duration, while the frequency of trains is often somewhat increased as the resting membrane potential in the intervals between spike trains is less negative by 6.5 mV. Glibenclamide (10(-7) M) did not affect the resting membrane potential or spontaneous mechanical activity of oxygenated portal veins, but partly restored the depressed myogenic activity in the presence of cyanide (0.5 mM). The spike trains were longer, while the membrane was depolarized by 3 mV compared with the effects of cyanide alone. Inhibition of both oxidative and glycolytic metabolism by 2 mM NaCN in a medium where glucose was replaced by beta-hydroxybutyrate caused a hyperpolarization which was abolished by 10(-7) M glibenclamide. The relaxing effect of the K+ channel opener cromakalim (5 x 10(-9) to 6.25 x 10(-7) M) was partly antagonized by glibenclamide. Basal cytosolic [Ca2+] was increased by cyanide, while the Ca2+ transients associated with phasic contractions were reduced in duration. This latter effect was partially reversed by glibenclamide. The effect of cyanide on high-K+ contractures, which are associated with sustained membrane depolarization and not dependent on repetitive spike activity, was not influenced by 10(-7) M glibenclamide. The effects of inhibited cell respiration on spontaneous electrical activity seem to reflect a depolarizing drive caused by inhibited active ion exchange mechanisms, modified by a repolarizing drive, possibly from ATP-regulated K+ channels, causing reduced duration of the spike trains. While glibenclamide affects spontaneous activity at all levels of oxidative blockade, glibenclamide-sensitive hyperpolarization is seen only when both oxidative and glycolytic metabolism is inhibited.
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| 44. |
- Lydrup, M L, et al.
(författare)
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Effects of extracellular K+ and Ca2+ on membrane potential, contraction and 86Rb+ efflux in guinea-pig mesotubarium
- 1990
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Ingår i: Pflügers Archiv. - 0031-6768. ; 415:6, s. 664-670
-
Tidskriftsartikel (refereegranskat)abstract
- The effects of varying extracellular concentrations of K+ and Ca2+ [K+]o and [Ca2+]o on force development and membrane potential were investigated in the guinea-pig mesotubarium. At [K+]o up to 40 mM, spontaneous action potentials were present, while higher [K+]o gave sustained contractures at a stable membrane potential (-24 to -12 mV for [K+]o from 60 to 120 mM). Tension decreased successively with increasing [K+]o from 30 to 120 mM. The relaxing potency of the dihydropyridine Ca2+ antagonist, felodipine, increased as the membrane was depolarized with increasing [K+]o and action potentials ceased. These results are compatible with the existence of Ca2+ channels showing voltage-dependent affinity with dihydrophyridines. Increasing [Ca2+]o from 2.5 to 10 mM caused membrane hyperpolarization by about 11 mV and was accompanied by a lower frequency of spontaneous contractions and a longer duration of the relaxation between contractions. 86Rb+ efflux measurements in 60 mM K+ in the absence and presence of felodipine revealed a Ca2(+)-dependent component of the voltage-activated efflux. In normal solution (5.9 mM K+), efflux in the presence of felodipine was similar to the minimal value during normal spontaneous activity. The results indicate regulation of the permeability of K+ channels by the intracellular Ca2+ concentration ([Ca2+]i) and suggest participation of such channels in the generation of the regularly occurring bursts of action potentials characteristic of spontaneous activity in the mesotubarium.
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| 45. |
- Lydrup, M L, et al.
(författare)
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Metabolic correlates to pacemaker activity in the smooth muscle of guinea-pig mesotubarium
- 1991
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 141:2, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- Oxygen consumption (FO2) and lactate production (Flac) were measured during spontaneous activity in the guinea-pig mesotubarium. During spontaneous contractions FO2 increased to maximally 0.270 +/- 0.025 mumol min-1g-1 (n = 23), followed by a rapid fall immediately upon relaxation. In the relaxed period (5-15 min) between spontaneous contractions FO2 continued to slowly decrease by about 25% towards a final value of 0.150 +/- 0.01 mumol min-1g-1. Flac showed no consistent variation during the relaxed period. Ouabain (10(-6)M) produced a contracture, which was abolished by the Ca2(+)-antagonist felodipine (10(-6)M). In the presence of felodipine, addition of ouabain caused depolarization and a decrease of oxygen consumption by 21% and of lactate production by 31%. Exchange of glucose in the physiological Krebs solution for beta-hydroxybutyrate did not influence spontaneous activity, while subsequent addition of cyanide (2 mM) abolished contractions and caused a hyperpolarization of 15 mV. Blockade of ATP-dependent K+ channels by addition of glibenclamide (10(-7)M) to the relaxed muscle in this situation caused spontaneous contractile activity to reappear. In glucose-containing Krebs solution glibenclamide had no effect on the spontaneous contractile and electrical activity and contractions persisted after addition of cyanide. The relaxing and hyperpolarizing effect of pinacidil could be counteracted by addition of glibenclamide. The results suggest that a decrease in electrogenic Na+/K(+)-pump activity in the course of the relaxed period between contractions could contribute to the pacemaker behaviour. ATP-dependent K+ channels, while having little influence on the spontaneous contractile activity under normal metabolic conditions, could be activated during blockade of aerobic and anaerobic metabolism, leading to inhibition of pacemaker activity.
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| 46. |
- Lydrup, M L, et al.
(författare)
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Paradoxical decrease in cytosolic calcium with increasing depolarization by potassium in guinea-pig mesotubarium smooth muscle
- 1992
-
Ingår i: Pflügers Archiv. - 0031-6768. ; 420:5-6, s. 428-433
-
Tidskriftsartikel (refereegranskat)abstract
- The free intracellular Ca2+ concentration ([Ca2+]i) was measured simultaneously with isometric force in strips of guinea-pig mesotubarium using the Fura-2 technique. [Ca2+]i and force were maximal at a relatively low (30 mM) concentration of extracellular K+ ([K+]o), and declined at 90 and 140 mM K+. Plateau values of both [Ca2+]i and force were higher in the presence of 5.10(-6) M ryanodine, indicating that the sarcoplasmic reticulum (SR) contributes to the decline with depolarization. Force and [Ca2+]i at 90 mM K+ were both lower then the high-K+ solution was applied after a period in 30 mM K+ than after a period in normal solution (5.9 mM K+), consistent with inactivation of Ca2+ channels during prolonged depolarization. Addition of carbachol to the depolarized muscle caused a maintained increase in force without maintained increase in [Ca2+]i. We conclude that the decrease in force at increased [K+]o (the "calcium-potassium paradox") is due to a membrane-potential-mediated decrease in [Ca2+]i and, to a lesser extent, to desensitization of the contractile-regulatory apparatus to Ca2+.
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| 47. |
- Lydrup, M L, et al.
(författare)
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Rate of oxidative and glycolytic metabolism in the guinea-pig oviduct in relation to contractility and hormonal cycle
- 1986
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 128:4, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- The rates of oxygen consumption and lactate production in the guinea-pig oviduct were measured together with registration of contractile activity during three phases of the hormonal cycle. In pro-oestrus (high oestrogen, low progesterone levels) and oestrus (time of ovulation, high oestrogen and progesterone) the rate of O2 consumption was higher than in dioestrus (low oestrogen, high progesterone). The frequency of spontaneous contractions was higher in oestrus than in the other phases. No significant differences in the proportion of the cross-sectional area occupied by smooth muscle were found between oviducts in di- and pro-oestrus. Stimulation by phenylephrine caused decreased frequency and increased amplitude of contractions in dioestrus but not in pro-oestrus, suggesting hormonal modulation of adrenergic mechanisms. The rate of relaxation of high-K+ contractures was higher in pro- than dioestrus. Lactate production and contents of ATP, ADP and phosphocreatine showed no significant variation with hormonal state. The increased rate of oxidative metabolism under oestrogenic dominance could in part reflect changes in ionic transport mechanisms, such as intracellular Ca2+ handling.
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| 48. |
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| 49. |
- Martner, Anna, 1979, et al.
(författare)
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Transient and durable T cell reactivity after COVID-19
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 119:30
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Tidskriftsartikel (refereegranskat)abstract
- This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until similar to 70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-gamma remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (T-H) cells followed by an equally synchronous and durable T(H)1-like reactivity reflecting long-lasting T cell memory.
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| 50. |
- Meisl, Georg, et al.
(författare)
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Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides.
- 2014
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:26, s. 9384-9389
-
Tidskriftsartikel (refereegranskat)abstract
- The two major forms of the amyloid-beta (Aβ) peptide found in plaques in patients suffering from Alzheimer's disease, Aβ40 and Aβ42, only differ by two amino acids in the C-terminal region, yet they display markedly different aggregation behavior. The origins of these differences have remained challenging to connect to specific molecular-level processes underlying the aggregation reaction. In this paper we use a general strategy to apply the conventional workflow of chemical kinetics to the aggregation of the Aβ40 peptide to identify the differences between Aβ40 and Aβ42 in terms of the microscopic determinants of the aggregation reaction. Our results reveal that the major source of aggregates in the case of Aβ40 is a fibril-catalyzed nucleation process, the multistep nature of which is evident through its saturation behavior. Moreover, our results show that the significant differences in the observed behavior of the two proteins originate not simply from a uniform increase in all microscopic rates for Aβ42 compared with Aβ40, but rather are due to a shift of more than one order of magnitude in the relative importance of primary nucleation versus fibril-catalyzed secondary nucleation processes. This analysis sheds light on the microscopic determinants of the aggregation behavior of the principal forms of Aβ and outlines a general approach toward achieving an understanding at the molecular level of the aberrant deposition of insoluble peptides in neurodegenerative disorders.
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