| 1. |
- Blennow, Kaj, 1958, et al.
(författare)
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No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.
- 2000
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 107:8-9, s. 1065-79
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Tidskriftsartikel (refereegranskat)abstract
- A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
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| 2. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos.
- 2002
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 10:2, s. 113-8
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.
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| 3. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Influence of the apolipoprotein E epsilon4 allele on human embryonic development.
- 2002
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Ingår i: Neuroscience letters. - 0304-3940. ; 324:3, s. 189-92
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Tidskriftsartikel (refereegranskat)abstract
- Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimer's disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.
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| 4. |
- Campagnoli, Monica, et al.
(författare)
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A novel splicing mutation causes an undescribed type of analbuminemia.
- 2002
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Ingår i: Biochimica et biophysica acta. - 0006-3002. ; 1586:1, s. 43-9
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Tidskriftsartikel (refereegranskat)abstract
- Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous subjects. In this report we describe a new molecular defect that caused the analbuminemic trait in a newborn of Iraqi origin. When the parents' DNA was analyzed, both subjects were found to be heterozygous for the same mutation found in the infant. All the 14 exon and flanking intron sequences of the albumin gene were amplified via PCR and screened for mutations by SSCP and heteroduplex analysis. A mutation in the DNA region encoding exon 1 and its flanking intron was revealed by the presence of a heteroduplex. The fragment, which was directly DNA sequenced, contains a previously unreported single nucleotide change, consisting in a G to A substitution at nucleotide 118 in the structural gene of the human protein. This mutation, involving the first base of intron 1, destroys the GT dinucleotide consensus sequence found at the 5' end of most intervening sequences and causes the defective pre-mRNA splicing responsible for the analbuminemic trait.
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| 5. |
- Carlsson, Per-Anders, 1972, et al.
(författare)
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A transient in situ FTIR and XANES study of CO oxidation over Pt/Al2O3 catalysts
- 2004
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Ingår i: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 226:2, s. 422-434
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Tidskriftsartikel (refereegranskat)abstract
- We report experimental results for the oxidation of CO over supported Pt/Al2O3 catalysts operating in oxygen excess at atmospheric pressure. To study the reaction kinetics under transient conditions we have employed step changes of the O2 concentration by intermittently switching off the O2 supply at various temperatures ranging from 523 to 623 K. Detailed in situ FTIR and XANES data for CO coverage and the chemical state of Pt, respectively, are presented together with the CO conversion, which in both cases was monitored by mass spectrometry. A red-shift of the vibrational frequency of linearly bonded CO which correlates with a blue-shift of the Pt LIII binding energy indicates that the Pt catalyst initially is partially oxidised and gradually reduced when the O2 supply is switched off. Control experiments with a NO2 oxidised Pt/Al2O3 catalyst support these findings. A hysteresis in the catalytic activity due to the different rates whereby Pt is oxidised and reduced as a function of gas-phase composition is observed. The activation energy for the Pt oxide reduction (decomposition) process is estimated to be about 50 kJ/mol. The results further emphasise that the conventional three-step Langmuir-Hinshelwood (LH) scheme used to interpret CO oxidation on Pt surfaces must be complemented by a Pt oxidation and reduction mechanism during transient conditions. Moreover, FTIR data suggest that during the extinction, the partially oxidised platinum surface is reduced by chemisorbed CO which should be explicitly accounted for in the modeling of the reaction mechanism.
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| 6. |
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| 7. |
- Hardling, Mats, et al.
(författare)
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Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate
- 2004
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Ingår i: Med Oncol. - 1357-0560. ; 21:4, s. 349-58
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Tidskriftsartikel (refereegranskat)abstract
- Survival among chronic myelogenous leukemia (CML) patients can be linked to the reduction in leukemic cell burden. Treatment with imatinib mesylate results in a high frequency of complete cytogenetic response, which can be further stratified using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We have serially monitored peripheral blood and bone marrow BCR-ABL transcripts using qRT-PCR in CML patients commencing imatinib therapy, and compared the results with bone marrow cytogenetics. Seventeen patients (aged 25-74 yr) with Philadelphia chromosome positive CML in first chronic phase were treated with imatinib targeting a dose of 400 mg/d. The median follow up is 30 mo (range 9-33 mo). Every third month the product of the BCR-ABL fusion gene was evaluated in both blood and bone marrow specimens by real-time RT-PCR using the TaqMan probe system. In 113 simultaneously obtained blood and bone marrow samples, the BCR-ABL transcript values agreed well with cytogenetic data. Blood and bone marrow specimens gave comparable values for BCR-ABL transcripts. Before start of imatinib therapy there was a considerable variation in BCR-ABL transcripts among the patients, ranging approximately one log (base 10). Similarly, patients with a complete cytogenetic response following imatinib therapy had variable BCR-ABL transcript levels, ranging at least three logs (base 10). The major decline in BCR-ABL transcripts occurred within 6 mo after start of imatinib therapy. The decline in BCR-ABL transcripts, following imatinib therapy, appears to level off at 12-15 mo. Two late responders were identified with a still decreasing level in BCR-ABL transcripts after 24 mo of treatment. It is concluded that BCR-ABL mRNA quantification in peripheral blood is suitable for routine monitoring of the response to treatment and long-term disease status in CML, especially in patients who have achieved a complete cytogenetic response. A plateau in BCR-ABL transcripts seems to have been reached after 12-15 mo of imatinib treatment; however, some "late responders" are seen.
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| 8. |
- Jansson, Jonas, 1973, et al.
(författare)
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On the catalytic activity of Co3O4 in low-temperature CO oxidation
- 2002
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Ingår i: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 211:2, s. 387-397
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Tidskriftsartikel (refereegranskat)abstract
- Oxidation of CO over Co3O4 at ambient temperature was studied with flow reactor experiments, and in-situ spectroscopic and structural methods. The catalyst deactivates during the reaction. The rate of deactivation increased with increasing CO or CO2 gas-phase concentration but decreased with increased 02 concentration or increased temperature. Regeneration of the catalyst in 10% O-2/Ar was more efficient than regeneration in Ar alone. The presence of carbonates and surface carbon on the deactivated catalyst was concluded from TPO experiments. None of these species could, however, be correlated with the deactivation of the catalyst. In-situ FTIR showed the presence of surface carbonates, carbonyl, and oxygen species. The change in structure and oxidation state of the catalyst was studied by in-situ XRD, in-situ XANES, XPS, and flow reactor experiments. One possible explanation for the deactivation of the catalyst is a surface reconstruction hindering the redox cycle of the reaction. (C) 2002 Elsevier Science (USA).
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| 9. |
- Johansson, Peter, 1958, et al.
(författare)
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Increased risk for vascular complications in PRV-1 positive patients with essential thrombocythaemia.
- 2003
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Ingår i: British journal of haematology. - 0007-1048. ; 123:3, s. 513-6
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Tidskriftsartikel (refereegranskat)abstract
- Essential thrombocythaemia (ET) is a heterogeneous disorder with respect to plasma erythropoietin concentration at diagnosis and clonality of haematopoiesis. Polycythaemia rubra vera-1 (PRV-1) positivity, i.e. PRV-1 mRNA overexpression, is known to be present in the vast majority of patients with polycythaemia vera and also in some patients with ET. In the present study, PRV-1 expression was quantified by real-time polymerase chain reaction in 70 ET patients; 17 of them (24%) were found to be PRV-1 positive. Ten of the 17 PRV-1 positive ET patients had experienced thromboembolic complications compared with 14 of 53 PRV-1 negative patients, the difference between the two groups being statistically significant (P=0.02). In addition, the frequency of total vascular complications, thromboembolic events and major bleedings, was significantly higher in the group of PRV-1 positive as compared with PRV-1 negative ET patients (P=0.03). The time from diagnosis of ET to the requirement of platelet-lowering therapy was significantly shorter in PRV-1 positive compared with PRV-1 negative ET patients (P=0.014). It can be concluded that PRV-1 positive patients appear to suffer from a more aggressive disorder with increased risk for vascular complications and a greater need for platelet-lowering therapy, compared with PRV-1 negative ET patients.
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| 10. |
- Johansson, Peter, 1958, et al.
(författare)
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The presence of a significant association between elevated PRV-1 mRNA expression and low plasma erythropoietin concentration in essential thrombocythaemia.
- 2003
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Ingår i: European journal of haematology. - 0902-4441. ; 70:6, s. 358-62
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 45% of newly diagnosed patients with essential thrombocythaemia (ET) demonstrate subnormal plasma erythropoietin (EPO) concentrations, which constitutes a risk factor for occlusive vascular events. In 58 ET patients, a possible association between polycythaemia rubra vera-1 (PRV-1) overexpression and subnormal plasma EPO was investigated, which was always measured prior to the institution of platelet lowering agents. At the time when PRV-1 expression was measured, 28 of 58 (48%) ET patients had received platelet lowering treatment. PRV-1 expression was measured by quantitative real-time reverse transcription-polymerase chain reaction assay of mRNA extracted from purified peripheral blood buffy coat. The cycle threshold (CT) value of PRV-1 was determined and was divided with the CT value for the housekeeping GAPDH gene transcript. A quotient <0.93 was defined as PRV-1 positive. Of the ET patients 12 of 58 (21%) were PRV-1 positive and 19 of 58 (33%) demonstrated subnormal plasma EPO. In the 58 ET patients there was a significant association between low plasma EPO and PRV-1 positive results (P = 0.001). The 30 ET patients who had not received any platelet lowering treatment showed a significant (P = 0.005) relation between PRV-1 positivity and subnormal plasma EPO. No such relationship was present in the 28 ET patients who had received prior treatment with the above drugs (P = 0.147).
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| 11. |
- Jones, Dylan T, et al.
(författare)
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Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis.
- 2003
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 101:8, s. 3174-80
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes apoptosis in diverse cellular systems. We previously showed that human plasma activated AKT and potently blocked the ability of chlorambucil or gamma radiation to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report experiments that identify albumin as the major component of plasma that blocks CLL cell killing by chlorambucil or radiation. Intact plasma depleted of albumin by chromatography on Cibacron blue-Sepharose or plasma from a subject with analbuminemia failed either to activate AKT or to protect CLL cells from chlorambucil-induced apoptosis. Both functions were restored by re-addition of albumin. The protective action of albumin as well as AKT activation was compromised by the binding of lipids. Fluorescence-activated cell sorter (FACScan) analysis demonstrated the uptake of fluoresceinated albumin by CLL cells. Accumulation of albumin in intracellular vesicles was also shown by confocal microscopy. Indirect inhibition of AKT activation by the phosphatidylinositol 3-kinase inhibitor LY294002 reversed the blockade of chlorambucil-induced killing by plasma albumin. The data suggest that activation of AKT consequent to binding of albumin by CLL cells blocks chlorambucil- and radiation-induced apoptosis. Strategies designed to block albumin-induced antiapoptotic signaling may, therefore, be of value in enhancing cytotoxic drug action on CLL cells.
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| 12. |
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| 13. |
- Palmqvist, Lars, 1965
(författare)
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Transcriptional regulation of the latent membrane protein 1 gene by Epstein-Barr virus nuclear antigen 2
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Epstein-Barr virus (EBV) is a ubiquitous human herpes virus, which infects B-cells. This leads to a life-long latent infection, which in most cases is non-pathogenic. However, EBV is etiologically associated with several human malignancies, including endemic Burkitt's lymphoma, nasopharyngeal carcinoma and post-transplant lymphoma. This association is probably linked to the ability of the virus to immortalise B-cells in vitro and to induce B-cell proliferation. Mutagenesis of the viral genome has defined a subset of four nuclear proteins (EBNA1, 2, 3, and 6) and one membrane protein (LMP1) required for the immortalisation process. The aim of the present study was to increase our knowledge about the different mechanisms by which the expression of the LMP1 gene is regulated in B-cells focussing on the role played by the virally encoded transactivating factor EBNA2. The importance of an ATF/CRE site and an Sp site in the proximal part of the LMP1 regulatory sequence (LRS) was established. Mutations of the ATF/CRE and Sp sites decreased both EBNA2-dependent and -independent LMP1 promoter activity in transient transfection experiments. Both cAMP and okadaic acid, an inhibitor of protein phosphatase 1 (PP1) and 2A (PP2A), activated the promoter in an ATF/CRE-dependent fashion. Immunoaffinity experiments showed that EBNA2 co-purified with a PP1-like protein from an EBV-immortalised B-cell line and that a recombinant EBNA2 fusion protein specifically bound and inhibited a PP1-like activity in B-cell extracts. Thus, we conclude that the ATF/CRE and Sp site is important in transactivation of the LMP1 promoter and that the ability of EBNA2 to block the effect exerted by protein phosphatases on a certain transcription factor can be part of the mechanism by which the LMP1 promoter is activated.Electrophoretic mobility shift assays showed that both the positive Sp1 and the negative Sp3 transcription factor bound to the Sp site. However, overexpression of the Sp1 transcription factor did not add to the activity induced by EBNA2. The heterodimeric transcription factor complexes ATF1/CREB1 and c-Jun/ATF2 bound to the ATF1/CRE site in LRS. The binding of ATF1/CREB1 activated the LMP1 promoter in the absence of EBNA2. The ATF2 and c-Jun transcription factors, on the other hand, did not activate the LMP1 promoter in the absence of EBNA2 but did so in the presence of EBNA2. The activating effect was abolished if the phosphate-accepting amino acid residues Thr69 and Thr71 in ATF2 were mutated. Furthermore, EBNA2 could interact with the c-Jun/ATF2 heterodimer. We conclude that EBNA2 is targeted to the promoter by these factors to transactivate the LMP1 promoter.Histone acetylation at the LMP1 promoter was studied in two different B-cell lines. Both EBNA2 and the histone deacetylase inhibitor Trichostatin A (TSA) rapidly increased the level of histone acetylation at the LMP1 promoter in resting ER/EB2-5 B-cells. However, only EBNA2 induced LMP1 transcription. This was in contrast to the situation in proliferating P3HR1 B-cells, in which TSA both increased histone acetylation at and activated transcription from the LMP1 promoter. Mutational analysis of LRS showed that the ATF/CRE element was an important mediator of the TSA effect. Our results also suggest that both EBNA2 and TSA require the presence of phosphorylated ATF2 to activate the LMP1 promoter.
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