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| 2. |
- Deisenhammer, F, et al.
(författare)
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Prediction of natalizumab anti-drug antibodies persistency
- 2019
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 25:3, s. 392-398
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Tidskriftsartikel (refereegranskat)abstract
- Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency. Design/methods: We developed a highly sensitive natalizumab ADA titration assay on the Meso Scale Discovery (MSD) platform and a pharmacokinetic (PK) assay. We included 43 patients with a positive ELISA-ADA result within 6 months of treatment initiation (baseline) of whom a follow-up serum sample was available 12–30 months after treatment start. MSD-ADA titres and drug levels were measured. Results: Median MSD-ADA titre at baseline was 4881 and 303 at follow-up. A titre of >400 at baseline had a 94% sensitivity and 89% specificity to predict ADA persistency. Reversion to ADA negativity occurred in 10 patients with mean drug levels of 10.8 μg/mL. The median trough drug level in ADA-positive samples was 0 µg/mL. PK levels and ADA titres correlated strongly negatively ( r = −0.67). Conclusion: High baseline natalizumab ADA titres accurately predict persistency. Despite continuous treatment, the majority of patients with persistent ADA had no detectable drug levels indicating loss of efficacy in line with phase 3 study results.
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| 10. |
- Ryner, M., et al.
(författare)
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Mechanism of ring-opening polymerization of 1,5-dioxepan-2-one and L-lactide with stannous 2-ethylhexanoate. A theoretical study
- 2001
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Ingår i: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; 34:12, s. 3877-3881
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Tidskriftsartikel (refereegranskat)abstract
- A theoretical study of the ring-opening polymerization (ROP) mechanism of 1,5-dioxepana-2-one (DXO) and (L)-lactide (LLA) with stannous(IE) a-ethylhexanoate (Sn(Oct)(2)) is presented. The B3LYP density functional method has been used for the quantum chemical calculations. Our results support a coordination-insertion mechanism initiated by a tin-alkoxide species formed prior to the ROP. The rate-determining step in the ROP was the nucleophilic attack of the alkoxide on the carbonyl carbon of the monomer. The activation energy for the ROP of DXO with Sn(Oct ')(2) has been determined to be 19.8 kcal/mol and for L-lactide 20.6 kcal/mol. At normal reaction temperatures, a ligand may dissociate as Oct 'H during propagation. An excess of carboxylic acid hinders the coordination of monomer to the initiating/propagating complex.
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| 11. |
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| 12. |
- von Schenck, H., et al.
(författare)
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Ring-opening polymerization of lactones and lactides with Sn(IV) and Al(III) initiators
- 2002
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Ingår i: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; 35:5, s. 1556-1562
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Tidskriftsartikel (refereegranskat)abstract
- A theoretical study is presented of the ring-opening polymerization (ROP) mechanism of 1,5-dioxepan-2-one (DXO) and glycolide with Sn(II) and Al(III) alkoxide initiators (SnMe3MeO, SnMe2-(MeO)(2), and AlMe2MeO). The B3LYP density functional method has been used to perform the quantum chemical calculations. A coordination-insertion mechanism is presented with two principal reaction steps. First, the alkoxide of the initiator performs a nucleophilic attack on the carbonyl carbon, and the carbonyl bond is broken. An intermediate is formed at this point, where the former carbonyl oxygen of the monomer is coordinated to tin via an alkoxide bond, while the carbonyl carbon assumes a sp(3) bonding geometry. The second step involves the acyl-oxygen cleavage of the monomer. For all three initiators it was found that the transition state involving the breaking of the carbonyl double bond (TS1) represented the highest point on the potential energy surface for DXO. For glycolide, however, the transition state of the acyl-oxygen cleavage (TS2) was the least stable structure. The reaction barriers were calculated to 17.1 kcal/mol for DXO/SnMe3MeO, 18.7 kcal/mol for glycolide/SnMe3MeO, 14.3 kcal/mol for DXO/SnMe2(MeO)(2), 14.5 kcal/mol for glycolide/SnMe2(MeO)(2), 13.6 kcal/mol for DXO/AlMe2MeO, and 9.3 kcal/mol for glycolide/AlMe2MeO. Both electronic and steric properties of the monomer affect the reaction barriers. It was found that the more electrophilic initiators polymerized cyclic esters faster.
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| 13. |
- Bengtsson, Erik, 1984, et al.
(författare)
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The (International) Political Economy of Falling Wage Shares: Situating Working-Class Agency
- 2015
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Ingår i: New Political Economy. - : Informa UK Limited. - 1356-3467 .- 1469-9923. ; 20:3, s. 406-430
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Tidskriftsartikel (refereegranskat)abstract
- This paper relates the financial and monetary dimensions of the contemporary economic crisis to working-class agency via a central concern of classical political economy: the distribution of surplus between the chief factors of production. The fall in the wage share of value added is now accepted as a stylised fact in the empirical economic literature. This paper argues that the punctuated pattern of the development validates the regulation theoretical narrative of an epochal shift from Fordism to finance-led accumulation. Furthermore, synthesising econometric studies supports a class-centred explanation. In the last instance, the falling wage share is due to successful transnational class rule in the form of a neoliberal hegemonic paradigm. Crucially, such class rule restructured the environment of trade unions, rendering increasingly ineffective its relational power resources. The paper concludes by considering the contradictory implications for organised labour of the current financial crisis. On the one hand, the financial crisis offers an opportunity to link its particular interests to the general interest of macroeconomic management since low wage share inhibits growth rates. But how might trade unions assert a higher wage share in the face of the structural power of (financial) capital? © 2014, © 2014 Taylor & Francis.
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| 14. |
- Dunn, N, et al.
(författare)
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Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies
- 2018
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 24:9, s. 1224-1233
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown. Objective: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients. Methods: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house–validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records. Results: ADAs were detected in 37% of relapsing–remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive. Conclusion: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.
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| 18. |
- Finne Wistrand, Anna, et al.
(författare)
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Degradable polymers : Design, synthesis and testing
- 2003
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Ingår i: Macromolecular Symposia. - : Wiley. - 1022-1360 .- 1521-3900. ; 195, s. 241-246
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Tidskriftsartikel (refereegranskat)abstract
- The object for our research is to mimic Nature's perfectly designed resorbable materials to obtain important materials, which are biocompatible and degradable. We have therefore synthesized different architectures and copolymers of aliphatic polyesters with ring-opening polymerization. The first studies of these materials properties show that properties like hydrophilicity and tensile properties can be controlled.
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| 19. |
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| 20. |
- Hedstrom, AK, et al.
(författare)
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Smoking and risk of treatment-induced neutralizing antibodies to interferon β-1a
- 2014
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 20:4, s. 445-450
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Tidskriftsartikel (refereegranskat)abstract
- Neutralizing antibodies (NAbs) to interferon β (IFNβ) products that develop during treatment are associated with a loss of clinical efficacy. Objectives: The aim of this study was to investigate the influence of smoking habits on the risk of developing NAbs to IFNβ, in the treatment of multiple sclerosis (MS). Methods: This report is based on 695 MS patients treated with IFNβ-1a, included in two Swedish case-control studies that collected information on smoking habits. Using logistic regression, the development of NAbs to IFNβ-1a among current smokers was compared with that of non-smokers, by calculating the odds ratio (OR) with a 95% confidence interval (CI). Results: Current smokers showed an increased risk of developing NAbs to IFNβ-1a, compared with non-smokers (OR 1.9; 95% CI 1.3–2.8; p = 0.002). There were no gender differences. We observed no association between past smoking and the risk of developing NAbs to IFNβ-1a. Conclusions: The finding that current smokers have an increased risk of developing NAbs to IFNβ-1a has implications, both for the practical care and the treatment of MS; it also provides an interesting perspective of the lungs as an immune-reactive organ, reacting upon irritation.
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| 21. |
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| 22. |
- Jensen, Poul Erik H., et al.
(författare)
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Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis : Results from the ABIRISK prospective cohort study
- 2019
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Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 326, s. 19-27
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Tidskriftsartikel (refereegranskat)abstract
- Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.
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| 23. |
- Kharlamova, N., et al.
(författare)
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Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n= 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n= 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 mu g/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 mu g/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 mu g/mL. ADA were seldom detected in patients with >1 mu g/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.
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| 24. |
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| 25. |
- Ryner, M., et al.
(författare)
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Resorbable and highly elastic block copolymers from 1,5-dioxepan-2-one and L-lactide with controlled tensile properties and hydrophilicity
- 2002
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 3:3, s. 601-608
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Tidskriftsartikel (refereegranskat)abstract
- New resorbable and elastomeric ABA tri- and multiblock copolymers have been successfully synthesized by combining ring-opening polymerization with ring-opening polycondensation. Five different Poly(L-lactide-b-1,5-dioxepan-2-one-b-L-lactide) triblock copolymers and one new Poly(L-lactide-b-1,5-dioxepan-2-one) multiblock copolymer have been synthesized. The triblock copolymers were obtained by ring-opening polymerization of 1,5-dioxepan-2-one (DXO) and L-lactide (LLA) with a cyclic tin initiator. The new multiblock copolymer was prepared by ring-opening polycondensation of a low molecular weight triblock copolymer with succinyl chloride. The molecular weight and the composition of the final copolymers were easily controlled by adjusting the monomer feed ratio, and all of the polymers obtained had a narrow molecular weight distribution. It was possible to tailor the hydrophilicity of the materials by changing the DXO content. Copolymers with a high DXO content had a more hydrophilic surface than those with a low DXO content, The receding contact angle varied from 27 to 44degrees. The tensile proper-ties of the copolymers were controlled by altering the PDXO block length. The tensile, testing showed that all the polymers were very elastic and had very high elongations-at-break (epsilon(b)). The copolymers retained very good mechanical properties (epsilon(b) approximate to 600-800% and sigma(b) approximate to 8-20 MPa) throughout the in vitro degradation study (59 days).
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| 26. |
- Ryner, M., et al.
(författare)
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Star-shaped and photocrosslinked poly(1,5-dioxepan-2-one) : Synthesis and characterization
- 2002
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Ingår i: Journal of Polymer Science Part A. - : Wiley. - 0887-624X .- 1099-0518. ; 40:12, s. 2049-2054
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Tidskriftsartikel (refereegranskat)abstract
- New star-shaped and photocrosslinked poly(1,5-dioxepan-2-one) (PDXO) has been synthesized through ring-opening polymerization initiated by SnOct(2)/pentaerythritol. The star-shaped PDXO was end-functionalized by acrolyol chloride to form acrylate end groups. The end-functionalized PDXO was photocrosslinked initiated by 2,2-dimethoxy-2-phenylacetophenone. The gel content ranged from 80 to 99%, indicating a high degree of crosslinking. The thermal properties of the star-shaped PDXO and the photocrosslinked PDXO were analyzed by differential scanning calorimetry. The glass-transition temperature was determined to approximately -32 degreesC for the crosslinked PDXO. The viscosity numbers were determined for star-shaped PDXO, with reference to linear homologues. The star-shaped PDXO had lower viscosity numbers than the linear counterparts, The crosslinked PDXO showed a rather hydrophilic surface as compared with other resorbable polyesters. The advancing contact angle was 64 +/- 2, and the receding angle was 57 +/- 4.
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| 27. |
- Ryner, M., et al.
(författare)
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Tailored mechanical properties and degradability of polyesters by controlled molecular architecture
- 2001
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Ingår i: Macromolecular Symposia. - 1022-1360 .- 1521-3900. ; 175, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- Advanced molecular architectures have been used as a toot for tailoring the mechanical properties and the degradation process of polymers for specific applications. Crosslinked poly(1,5-dioxepan-2-one), random poly(1,5-dioxepan-2-one-co-L-lactide), triblock poly(L-lactide-b-1,5-dioxepan-2-one-b-L-lactide) and triblock poly(epsilon -caprolactone-b-1,5-dioxepan-2-one-b-epsilon -caprolactone) have been synthesized and their thermal and mechanical properties as well as degradation times and degradation products have been characterized and compared. The stress at break of the synthesized polymers ranged from 4 MPa to 55 MPa and the elongation at break from 25% to 1200%. The degradation time varied from 70 days up to 360 days. These polymers are suitable as films or microspheres for controlled drug delivery or as temporary tissue replacements e.g. for tendons or nerve guides.
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| 28. |
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| 29. |
- Stridsberg, K., et al.
(författare)
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Dihydroxy-terminated poly(L-lactide) obtained by controlled ring-opening polymerization : Investigation of the polymerization mechanism
- 2000
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Ingår i: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; 33:8, s. 2862-2869
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Tidskriftsartikel (refereegranskat)abstract
- Hydroxy telechelic poly(L-lactide)s of different molecular weight have been synthesized by controlled ring-opening polymerization using cyclic tin alkoxides. NMR analysis showed that the propagation proceeded through an insertion mechanism. No free hydroxyl or carboxyl end groups were detected in the polymerization mixture. Complete reaction of the initiator was observed over the entire range of compositions studied. Both tin-oxygen bonds were reactive and participated in the propagation reaction. Peak assignments were obtained by H-1, C-13, distortionless enhancement polarization transfer (DEPT), and heteronuclear multiple quantum coherence-gradient selected (hmqc-gs) nuclear magnetic resonance spectroscopy. The kinetics of the solution polymerization of L-lactide has been investigated and showed a first order in monomer. The external order in initiator has been determined to be 3/4 for initiator concentrations above 5 mmol/L and to 2 below 2 mmol/L. The molecular weight could easily be adjusted by the monomer-to-initiator ratio, and the molecular weight distribution remained narrow even at high molecular weight(MWD < 1.15). The polymerization products were characterized by size exclusion chomatography (SEC) as well as H-1 and C-13 NMR.
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