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- Omazic, B, et al.
(författare)
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Reconstitution of the ig heavy chain CDR3 repertoire after allogeneic haematopoietic stem cell transplantation with myeloablative or reduced-intensity conditioning regimens
- 2005
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 61:1, s. 72-81
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate B-lymphocyte reconstitution in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. B-lymphocyte reconstitution was studied by monitoring the CDR3 repertoire with spectratyping. We demonstrate a delay in the recovery of the B-lymphocyte repertoire, measured by variation in size distribution of the immunoglobulin H CDR3 in patients conditioned with RIC compared to MAC. We found no general explanation for this finding, but when clinical data for each patient were studied in detail, we could identify a cause for the oligoclonality of the B-lymphocyte repertoire after HSCT with RIC for each of the patients. Older patients and donors, low cell dose at transplantation, relapse, graft-versus-host disease (GVHD) and its treatment as well as cytomegalovirus infection and its treatment are all possible causes for the restriction of the B-lymphocyte repertoire observed in this study. Taken together, reconstitution of the B-lymphocyte repertoire after HSCT is a process dependent on multiple factors and differs between patients. The conditioning regimen may be of importance, but data from this study suggest that individual factors and the various complications occurring after HSCT are more likely to determine the development of the B-lymphocyte repertoire.
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| 8. |
- Astermark, Jan, et al.
(författare)
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Effects of gamma-carboxyglutamic acid and epidermal growth factor-like modules of factor IX on factor X activation. Studies using proteolytic fragments of bovine factor IX
- 1992
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 267:5, s. 3249-3256
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Tidskriftsartikel (refereegranskat)abstract
- Factor IX is a vitamin K-dependent zymogen of a serine protease. The NH2-terminal half of the molecule consists of a Ca(2+)-binding gamma-carboxyglutamic acid (Gla)-containing module and two modules homologous to the epidermal growth factor (EGF) precursor. To elucidate the role of these non-catalytic modules of factor IXa beta in factor X activation, we have isolated and characterized fragments of bovine factor IX, containing one or both of the EGF-like modules as well as these modules linked to the Gla module. The fragments were used as inhibitors of factor IXa beta-mediated factor X activation in a plasma clotting system and in systems with purified components of the Xase complex. Fragments consisting of either the two EGF-like modules of factor IX linked together or the NH2-terminal EGF-like module alone were found to inhibit factor Xa generation both in the presence and absence of the cofactor, factor VIIIa. Moreover, a fragment consisting of the corresponding modules of factor X had a similar effect. We therefore propose that factor IXa beta and factor X interact directly through their EGF-like modules on or in the vicinity of a phospholipid surface. We have also found that the isolated Gla module of factor IX inhibits the formation of factor Xa both in the presence and absence of phospholipid but not in the absence of factor VIIIa. Our results are compatible with a model of the Xase complex, in which both the serine protease part and the Gla module of factor IXa beta interact with factor VIIIa.
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- Bjork, I, et al.
(författare)
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Differential changes in the association and dissociation rate constants for binding of cystatins to target proteinases occurring on N-terminal truncation of the inhibitors indicate that the interaction mechanism varies with different enzymes
- 1994
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Ingår i: Biochemical Journal. - 0264-6021. ; 299, s. 219-225
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Tidskriftsartikel (refereegranskat)abstract
- The importance of the N-terminal region of human cystatin C or chicken cystatin for the kinetics of interactions of the inhibitors with four cysteine proteinases was characterized. The association rate constants for the binding of recombinant human cystatin C to papain, ficin, actinidin and recombinant rat cathepsin B were 1.1 x 10(7), 7.0 x 10(6), 2.4 x 10(6) and 1.4 x 10(6) M-1.s-1, whereas the corresponding dissociation rate constants were 1.3 x 10(-7), 9.2 x 10(-6), 4.6 x 10(-2) and 3.5 x 10(-4) s-1. N-Terminal truncation of the first ten residues of the inhibitor negligibly affected the association rate constant with papain or ficin, but increased the dissociation rate constant approx. 3 x 10(4)- to 2 x 10(6)-fold. In contrast, such truncation decreased the association rate constant with cathepsin B approx. 60-fold, while minimally affecting the dissociation rate constant. With actinidin, the truncated cystatin C had both an approx. 15-fold lower association rate constant and an approx. 15-fold higher dissociation rate constant than the intact inhibitor. Similar results were obtained for intact and N-terminally truncated chicken cystatin. The decreased affinity of human cystatin C or chicken cystatin for cysteine proteinases after removal of the N-terminal region is thus due to either a decreased association rate constant or an increased dissociation rate constant, or both, depending on the enzyme. This behaviour indicates that the contribution of the N-terminal segment of the two inhibitors to the interaction mechanism varies with the target proteinase as a result of structural differences in the active-site region of the enzyme.
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| 22. |
- Ehrlund, A, et al.
(författare)
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The cell-type specific transcriptome in human adipose tissue and influence of obesity on adipocyte progenitors
- 2017
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Ingår i: Scientific data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4, s. 170164-
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Tidskriftsartikel (refereegranskat)abstract
- Obesity affects gene expression and metabolism of white adipose tissue (WAT), which results in insulin resistance (IR) and type 2 diabetes. However, WAT is a heterogeneous organ containing many cell types that might respond differently to obesity-induced changes. We performed flow cytometry sorting and RNA expression profiling by microarray of major WAT cell types (adipocytes, CD45−/CD31−/CD34+ progenitors, CD45+/CD14+ monocytes/ macrophages, CD45+/CD14− leukocytes), which allowed us to identify genes enriched in specific cell fractions. Additionally, we included adipocytes and adipocyte progenitor cells obtained from lean and obese individuals. Taken together, we provide a detailed gene expression atlas of major human adipose tissue resident cell types for clinical/basic research and using this dataset provide lists of cell-type specific genes that are of interest for metabolic research.
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| 23. |
- Elomaa, I, et al.
(författare)
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Five-year results in Ewing's sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol
- 2000
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Ingår i: European Journal of Cancer. - 1879-0852. ; 36:7, s. 875-880
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Tidskriftsartikel (refereegranskat)abstract
- The first Scandinavian protocol for Ewing's sarcoma, SSG IV, resulted in a local control rate of 74% and 5-year metastasis-free survival (MFS) of 43%. The second protocol, SSG IX, was started in order to improve upon these results. It featured four chemotherapy cycles, each consisting of two courses of VAI (vincristine, doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin, doxorubicin, ifosfamide) at 3-weekly intervals. Total treatment time was 35 weeks. Local therapy was given at week 9. Inoperable or non-radically operated patients received hyperfractionated accelerated radiotherapy 1.5 Gy twice daily between chemotherapy courses to a total dose of 42-60 Gy, depending on surgical radicality and tumour localisation. 88 patients were included (58 male, 30 female, mean age 20 years; range 5-65 years). The tumour (73 M0 and 15 M1) was located centrally in 31 patients (35%), in the extremities in 34 (39%) and other sites in 23 (26%) of cases. The median size of tumour was 10 cm (range 2-23), soft tissue was invaded in 87%. Surgery was the local therapy for 60 (68%) patients: amputation in 8 and local excision in 52. The surgical margins were wide in 35 patients, marginal in 14 and intralesional in 3. Radiotherapy was given to 17 non-radically operated patients postoperatively and to 28 patients with inoperable tumours primarily. Histological responses were evaluated in 52 patients. 9 local recurrences were observed (10%). Distant metastases developed in 24 M0 patients (33%). The estimated 5-year MFS was 58% and overall survival (OS) 70% for M0 and 27% and 28% for M1 patients, respectively. Survival was favourable in patients with non-metastatic extremity tumours (90%) and tumours operated with wide margins (90%). Patients with a total necrosis after chemotherapy had a better OS than those with a partial or poor response (P=0.003). The toxicity (World Health Organisation) was acceptable (gastrointestinal G1-2; haematological G3-4). The SSG IX protocol gave better local control and survival rates than the SSG IV. Whether this is due to a higher therapeutic efficacy of the present protocol cannot be ascertained in this comparison with a historical control.
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| 30. |
- Kreicbergs, Ulrika, et al.
(författare)
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Care-related distress: a nationwide study of parents who lost their child to cancer
- 2005
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Ingår i: J Clin Oncol. - 0732-183X .- 1527-7755. ; 23:36, s. 9162-71
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Palliative care is an important part of cancer treatment. However, little is known about how care-related factors affect bereaved intimates in a long-term perspective. We conducted a population-based, nationwide study addressing this issue, focusing on potential care-related stressors in parents losing a child to cancer. METHODS: In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer in 1992 to 1997. The parents were asked, through an anonymous postal questionnaire, about their experience of the care given and to what extent these experiences still affect them today. RESULTS: Information was supplied by 449 (80%) of 561 eligible parents. Among 196 parents of children whose pain could not be relieved, 111 (57%) were still affected by it 4 to 9 years after bereavement. Among 138 parents reporting that the child had a difficult moment of death, 78 (57%) were still affected by it at follow-up. The probability of parents reporting that their child had a difficult moment of death was increased (relative risk = 1.4; 95% CI, 1.0 to 1.8) if staff were not present at the moment of death. Ten percent of the parents (25 of 251 parents) were not satisfied with the care given during the last month at a pediatric hematology/oncology center; the corresponding figure for care at other hospitals was 20% (33 of 168 parents; P = .0163). CONCLUSION: Physical pain and the moment of death are two important issues to address in end-of-life care of children with cancer in trying to reduce long-term distress in bereaved parents.
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| 34. |
- Nycander, M, et al.
(författare)
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Two-step mechanism of inhibition of cathepsin B by cystatin C, due to the inhibitor displacing the occluding loop of the enzyme
- 1998
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Ingår i: FEBS Letters. - 1873-3468. ; 422:1, s. 61-64
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Tidskriftsartikel (refereegranskat)abstract
- Stopped-flow kinetics showed that the inhibition of the lysosomal cysteine proteinase, cathepsin B, by its endogenous inhibitor, cystatin C, occurs by a two-step mechanism, in which an initial, weak interaction is followed by a conformational change. The initial interaction most likely involves binding of the N-terminal region of the inhibitor to the proteinase. Considerable evidence indicates that the subsequent conformational change is due to the inhibitor displacing the occluding loop of the proteinase that partially obscures the active site. The presence of this loop, which allows the enzyme to function as an exopeptidase, thus complicates the inhibition mechanism, rendering cathepsin B much less susceptible than other cysteine proteinases to inhibition by cystatins.
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| 39. |
- Pavlova, A, et al.
(författare)
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Cystatin inhibition of cathepsin B requires dislocation of the proteinase occluding loop. Demonstration by release of loop anchoring through mutation of His110
- 2000
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Ingår i: FEBS Letters. - 1873-3468. ; 487:2, s. 156-156
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Tidskriftsartikel (refereegranskat)abstract
- Cystatins A and C were both shown to inhibit cathepsin B by a two-step mechanism, involving an initial weak interaction followed by a conformational change. Disruption of the major salt bridge anchoring the occluding loop of cathepsin B to the main body of the enzyme by mutation of His110 to Ala converted the binding to an apparent one-step reaction. The second step of cystatin binding to cathepsin B must therefore be due to the inhibitor having to alter the conformation of the enzyme by displacing the occluding loop to allow a tight complex to be formed. Cystatin A was appreciably less effective in displacing the loop than cystatin C, resulting in a considerably lower overall inhibition rate constant.
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| 40. |
- Persson, Kristina, et al.
(författare)
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Calcium binding to the first EGF-like module of human factor IX in a recombinant fragment containing residues 1-85. Mutations V46E and Q50E each manifest a negligible increase in calcium affinity
- 1998
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Ingår i: FEBS Letters. - 1873-3468. ; 421:2, s. 100-104
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Tidskriftsartikel (refereegranskat)abstract
- The first EGF-like module of human coagulation factor IX contains a single functionally important calcium ion binding site. We have now shown the dissociation constant for this site to be approximately 160 microM in a recombinant protein fragment consisting of residues 1-85 in human fIX. This represents a approximately 10-fold increase in affinity as compared with the isolated EGF module (residues 46-85). The Gla module (here with Glu instead of Gla) thus increases the affinity of the EGF module calcium ion binding site. Each of two mutations, V46E and Q50E, made to investigate whether the extra negative charge would increase the affinity of the calcium binding site manifested a negligible increase in affinity.
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- Sjöberg, Mats, et al.
(författare)
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Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients
- 2013
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley-Blackwell. - 0269-2813 .- 1365-2036. ; 38:4, s. 377-387
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRescue therapy with infliximab (IFX) has been proven effective in a steroid-refractory attack of ulcerative colitis (UC). The long-term efficacy is not well described. less thanbrgreater than less thanbrgreater thanAimTo present a retrospective study of IFX as rescue therapy in UC. Primary end points were colectomy-free survival at 3 and 12months. less thanbrgreater than less thanbrgreater thanMethodsIn this multicentre study, 211 adult patients hospitalised between 1999 and 2010 received IFX 5mg/kg as rescue therapy due to a steroid-refractory, moderate-to-severe attack of UC. Exclusion criteria were duration of current flare for andgt;12weeks, corticosteroid treatment for andgt;8weeks before hospitalisation, previous IFX therapy or Crohns disease. less thanbrgreater than less thanbrgreater thanResultsProbability of colectomy-free survival at 3months was 0.71 (95% CI, 0.64-0.77), at 12months 0.64 (95% CI, 0.57-0.70), at 3years 0.59 (95% CI, 0.52-0.66) and at 5years 0.53 (95% CI, 0.44-0.61). Steroid-free, clinical remission was achieved in 105/211 (50%) and 112/209 (54%) patients at 3 and 12months respectively. Of 75 colectomies during the first year, 48 (64%) were carried out during the first 14days, 13 (17%) on days 15-90 and 14 (19%) between 3 and 12months. There were three (1.4%) deaths during the first 3months. less thanbrgreater than less thanbrgreater thanConclusionsInfliximab is an effective rescue treatment, both short- and long-term, in a steroid-refractory attack of UC. Most IFX failures underwent surgery during the first 14days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare.
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