| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- 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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| 10. |
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