| 1. |
- Andersson, Malin E, 1978, et al.
(författare)
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Kinesin gene variability may affect tau phosphorylation in early Alzheimer's disease.
- 2007
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 20:2, s. 233-9
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Tidskriftsartikel (refereegranskat)abstract
- Kinesin is a microtubule-associated motor protein that transports Alzheimer-associated amyloid precursor protein (APP) in neurons. In animal models, impaired kinesin-mediated APP transport seems to enhance formation of the neurotoxic 42 amino acid fragment of beta-amyloid (A beta 42). In man, one study suggests that a polymorphism (rs8702, 56,836G>C) in the kinesin light chain 1 gene (KNS2) may affect the risk of Alzheimer's disease (AD). To further assess KNS2 as a susceptibility gene for AD we analyzed 802 patients with sporadic AD and 286 controls, 134 longitudinally followed patients with mild cognitive impairment (MCI) and 39 cognitively stable controls for the rs8702 polymorphism. The rs8702 polymorphism did not influence risk of AD (p=0.46). However, rs8702 interacted with APOE epsilon 4 carrier status in AD (p=0.006) and influenced cerebrospinal fluid levels of hyperphosphorylated tau in MCI patients who converted to AD during follow-up (p=0.018). These findings support earlier indications that genetic variability in the KNS2 gene may play a role during early stages of AD pathogenesis.
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| 2. |
- Böttiger, Anna K., 1977-, et al.
(författare)
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Association of total plasma homocysteine with methylenetetrahydrofolate reductase genotypes 677C > T, 1298A > C, and 1793G > A and the corresponding haplotypes in Swedish children and adolescents
- 2007
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Ingår i: International Journal of Molecular Medicine. - Athens, Greece : D.A. Spandidos. - 1107-3756 .- 1791-244X. ; 19:4, s. 659-665
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Tidskriftsartikel (refereegranskat)abstract
- We studied 692 Swedish children and adolescents (aged 9-10 or 15-16 years, respectively), in order to evaluate the effect of the methylenetetrahydrofolate reductase (MTHFR) 677C > T, 1298A > C, and 1793G > A polymorphisms on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing (TM) technology. The MTHFR 677C > T polymorphism was associated with increased tHcy concentrations in both the children and the adolescents (P < 0.001 for both age groups) in both genders. The effect of MTHFR 1298A > C was studied separately in subjects with the 677CC and 677CT genotypes, and the 1298C allele was found to be associated with higher tHcy levels both when children were stratified according to 677C > T genotypes, and when using haplotype analyses and diplotype reconstructions. The 1793A allele was in complete linkage disequilibrium with the 1298C allele. It was still possible to show that the 1793A allele was associated with lower tHcy levels, statistically significant in the adolescents. In conclusion, a haplotype-based approach was slightly superior in explaining the genetic interaction on tHcy plasma levels in children and adolescents than a simple genotype based approach (R-2 adj 0.44 vs. 0.40). The major genetic impact on tHcy concentrations is attributable to the MTHFR 677C > T polymorphism. The common 1298A > C polymorphism had a minor elevating effect on tHcy, whereas the 1793G > A polymorphism had a lowering effect on tHcy.
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| 3. |
- Böttiger, Anna K., et al.
(författare)
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Mutations in exons 2 and 3 of the FOLR1 gene in demented and non-demented elderly subjects
- 2007
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Ingår i: International Journal of Molecular Medicine. - Athens, Greece : D.A. Spandidos. - 1107-3756 .- 1791-244X. ; 20:5, s. 653-662
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported six novel mutations in the 5'-UTR of the gene for folate receptor-alpha (FOLR1). In our search for additional mutations we screened patients, referred for investigation of suspected dementia (DGM subgroup) by SSCP and DNA sequencing from the end of exon 1 to the first bases of intron 3. We found 4 sequence variations, FOLR1 g.1314G>A, g.1816delC, g.1841G>A, and g.1928C>T. Pyrosequencing genotyping assays were developed for all of them, and 389 active seniors (AS subgroup) and the 202 DGM patients were genotyped for these mutations. The frequency q of the mutated allele was, among the AS subjects, 0.068, 0.0026, 0.0026, and 0.024 respectively, and among the DGM subjects, 0.067, 0.0076, 0.0078, and 0.023. The g.1816delC and g.1841G>A mutations thus were more frequent in the DGM than in the AS subgroup, but the difference did not reach statistical significance. The mutated alleles, FOLR1 1816(-) and 1841A, always occurred together in the same subjects, suggestive of a rare double-mutant haplotype. The two common polymorphisms, FOLR1 g. 1314G>A and g.1928C>T seemed not to raise tHcy plasma levels, whereas the double-mutated g.1816(-)-g.1841A haplotype may possibly have a slight tHcy-raising effect. Thus, so far 8 novel rare FOLR1 mutations with a combined prevalence of approximately 1.3% in Whites as well as two common polymorphisms with 5% and 13%, respectively, have been demonstrated. Only a few of the rare mutations may potentially be associated with raised plasma tHcy concentrations. No association with dementia was found.
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| 4. |
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| 5. |
- Farnebo, Lovisa, et al.
(författare)
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Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines
- 2009
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 24:4, s. 549-556
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearsons correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p andlt;= 0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3(241) and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p andlt;= 0.001).
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| 6. |
- Fortin, Marc-André, et al.
(författare)
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Labelling chemistry and characterization of [90Y/177Lu]-DOTA-ZHER2:342-3 Affibody molecule, a candidate agent for locoregional treatment of urinary bladder carcinoma
- 2007
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Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 19:2, s. 285-291
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Tidskriftsartikel (refereegranskat)abstract
- The direct instillation of radiolabelled conjugates in the urinary bladder is a promising path for the treatment of bladder carcinoma. The targeting of HER2/neu receptors expressed on the surface of many bladder carcinoma cells shows potential to be developed as a therapeutic strategy, and patients identified with a high risk of progression may benefit from adjuvant targeted radionuclide therapy. A phage-display selected Affibody molecule (Z(HER2:342)) which binds to HER2/neu with picomolar affinity, can be used for targeting HER2/neu-expressing bladder carcinomas. A DOTA-derivative of Z(HER2:342), designated as DOTA-Z(HER2:342)-3, is considered as a suitable targeting agent for therapy. The DOTA chelator provides stable labelling with radiometals, and the low molecular weight (7.2 kDa) of the DOTA-Z(HER2:342)-3 compound is expected to enable efficient tumor penetration. DOTA-Z(HER2:342)-3 was radiolabelled with 90Y and 177Lu in 1 M ammonium acetate buffer, at pH 5.5, and in the presence of ascorbic acid. Nearly quantitative labelling yields were achieved for both nuclides after 15 min of incubation at 60 degrees C. After chelation, the conjugates retained their capacity to specifically bind to HER2/neu-expressing SKOV-3 cells. The radiolabelled affibody conjugate (DOTA-Z(HER2:342)-3) demonstrated high antigen-binding capacity and good cellular retention. Biodistribution in normal mice demonstrated low uptake in all organs and tissues except for kidneys.
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| 7. |
- Franzén, Lennart E., et al.
(författare)
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Characterization of colon carcinoma growth pattern by computerized morphometry : definition of a complexity index
- 2008
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 22:4, s. 465-472
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Tidskriftsartikel (refereegranskat)abstract
- The invasive front of carcinomas may vary in complexity from smooth to highly complex when the front splits up into small cell clusters or even single cancer cells. The degree of complexity is usually estimated visually and semiquantitatively by a pathologist, although more objective methods based on computer-assisted image analysis are available. In this study, we compared the visual estimation of the irregularity of the tumour invasion front of colon carcinomas to different quantitative image analytical techniques and defined a complexity index for the invasive margin. Sections from 29 archived colon carcinomas were stained immunohistochemically for cytokeratin 8. Images of the tumour invasion front were read into a computer and thresholded so that the tumour tissue became black and the background white or so that the tumour front was outlined by a single pixel line. The invasive front was visually classified into four degrees of irregularity by a pathologist. The complexity of the front was then assessed using four different image analysis techniques, i.e. the estimation of fractal dimension, tumour front length, number of tumour cell clusters and lacunarity. Fractal dimension and tumour cell clusters together gave the best correlation to visual grading using a discriminant analysis. A cluster analysis and a tree diagram analysis were then performed and were found to be superior to visual estimation. The clusters represent different degrees of complexity and the result of the tree diagram analysis can be used to assign complexity indices to colon tumours. The fractal dimension separated tumours up to a certain level (1.5-1.6) of complexity. When the tumour front split up into small cell clusters, the counting of tumour cell clusters separated the cells over and above the fractal dimension. This new technique can be used to objectively and quantitatively describe the complexity of the invasive front of tumours.
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| 8. |
- Hildenbrand, Anna, et al.
(författare)
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Aquaporin 1 is expressed in the human endometrium during normal cycle and increases after mifepristone treatment.
- 2008
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Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 22:1, s. 49-53
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporin-1 (AQP1) is involved in the angiogenesis and structural modifications of microvessels and possibly also in the pathogenesis of idiopathic menhorrhagia, where a reduced AQP1 expression is seen in the endometrium. Mifepristone treatment induces reduced menstrual bleeding and amenorrhea and also has a direct effect on endometrial arterioles. Administered with gestagen-only contraceptive methods, antiprogestins improve the bleeding pattern. The objective of this study was to evaluate the AQP1 expression in endometrial blood vessels during normal cycle and after mifepristone treatment. Localization and expression of AQP1 was determined using immunohistochemistry and reverse transcriptase chain reaction (RT-PCR) in 43 biopsies from human endometrium taken during a normal cycle and after mifepristone treatment. AQP1 expression in human endometrial vessels is not cycle dependent and is stronger in capillaries and arteries than in veins. After mifepristone treatment the staining intensity was increased, but not the number of stained vessels. The presence of AQP1 was also confirmed using RT-PCR. The changes in AQP1 expression could contribute to the reduced bleeding seen following mifepristone treatment and could be an effect of either antagonizing progesterone or cortisol.
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| 9. |
- Orlova, Anna, et al.
(författare)
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Pre-clinical evaluation of [111In]-benzyl-DOTA-Z(HER2:342), a potential agent for imaging of HER2 expression in malignant tumors
- 2007
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 20:3, s. 397-404
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Tidskriftsartikel (refereegranskat)abstract
- Imaging of expression of human epidermal growth factor receptor type 2 (HER2) in breast carcinomas may help to select patients eligible for trastuzumab therapy. The Affibody molecule Z(HER2:342) is a small (7-kDa) non-immunoglobulin affinity protein, which binds to HER2 with a picomolar affinity. Previously, a benzyl-DTPA conjugate of Z(HER2:342) was labeled with 111In and demonstrated good targeting in murine xenografts. We considered that the use of the macrocyclic chelator DOTA could increase the label stability and enhance a choice of nuclides, which could be used as a label for Z(HER2:342). The goal of this study was the preparation and pre-clinical evaluation of the indium-111- labeled DOTA-derivative of Z(HER2:342). Isothiocyanate-benzyl-DOTA was coupled to recombinant Z(HER2:342), and the conjugate was efficiently labeled with 111In at 60 degrees C. The specificity of 111In-benzyl-DOTA-Z(HER2:342) binding to HER2 was confirmed in vitro using HER2-expressing breast carcinoma BT474 and ovarian carcinoma SKOV-3 cell lines. Biodistribution of 111In-benzyl-DOTA-Z(HER2:342) was performed in nude mice bearing LS174T xenografts and compared directly with the biodistribution of 111In-benzyl-DTPA-Z(HER2:342). In vivo, 111In-benzyl-DOTA-Z(HER2:342) demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of 111In-benzyl-DOTA-Z(HER2:342) (4.4+/-1.0% IA/g) was specific and the tumor-to-blood ratio was 23. The use of benzyl-DTPA provided higher tumor-to-blood and tumor-to-liver ratios. gamma-camera imaging showed clear visualization of HER2-expressing xenografts using 111In-benzyl-DOTA-Z(HER2:342). 111In-benzyl-DOTA-Z(HER2:342) has a potential for imaging of HER2 expression in malignant tumors.
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| 10. |
- Samuelsson, Malin, et al.
(författare)
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β-Amyloid and interleukin-1β induce persistent NF-κB activation in rat primary glial cells
- 2005
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 16:3, s. 449-453
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Tidskriftsartikel (refereegranskat)abstract
- An increasing body of evidence suggests that β-amyloid (Aβ) and activated glial cells play a crucial part in the pathogenesis of Alzheimer's disease (AD). Activated glial cells surrounding the senile plaques, formed by Aβ peptides, have been proposed to promote neurodegeneration by producing putatively toxic factors, including the inflammatory cytokine interleukin-1β (IL-1β). Elevated levels of both IL-1β and activated nuclear factor κB (NF-κB), a key transcription factor regulating a wide variety of inflammatory genes, have been found in the brains of AD patients. In this study, we have investigated the ability of the Aβ(25-35) peptide and IL-1β, either alone or together, in activating NF-κB in glial cells. Mixed primary glial cells from rat were treated with IL-1β and/or Aβ(25-35), and NF-κB binding activity was analyzed by electophoretic mobility shift assay. We observed that the induction of NF-κB binding activity induced by either IL-1β or Aβ(25-35) showed a peak at 30 min, and significantly declined after 2 h. The induced NF-κB activation persisted after 24 h and even seemed to increase in cells treated with Aβ(25-35). The activation of NF-κB by Aβ(25-35) was shown to be dose-dependent. In addition, Aβ(25-35) potentiated the effect of IL-1β in a dose-dependent manner when co-stimulating the cells. The potentiating effect of Aβ(25-35) on IL-1β-induced NF-κB binding activity was observed after 30 min, 2 h and 24 h, and did not significantly differ over time. A possible explanation is that when glial cells are stimulated by inflammatory factors in the presence of Aβ peptides or senile plaques, the NF-κB negative feedback regulation is no longer functional.
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| 11. |
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| 12. |
- Tran, Thuy, et al.
(författare)
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Comparison of benzoate- and dodecaborate-based linkers for attachment of radioiodine to HER2-targeting Affibody ligand
- 2007
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Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 19:3, s. 485-493
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Tidskriftsartikel (refereegranskat)abstract
- The use of radionuclide molecular imaging enables the selection of patients for treatment using molecular medicine. Preclinical studies have demonstrated that a novel low-molecular-weight affinity ligand, Affibody molecule Z(HER2:342) can image the expression of HER2 with high sensitivity and specificity in tumour xenografts and has a potential for the selection of patients for treatment using Herceptin or other anti-HER2 medicine. In this study, we performed a comparative evaluation of two possible linkers for radioiodination of the Affibody molecule Z(HER2:342), 4-iodobenzoate (PIB) and [4-isothiocyanatobenzyl)-amino]-undecahydro-closo-dodecaborate (DABI). It was shown that the use of DABI makes it possible to obtain radioiodinated Z(HER2:342) with preserved capacity for selective binding to HER2-expressing cells. There was no difference between 125I-PIB-Z(HER2:342) and 125I-DABI-Z(HER2:342) in cellular retention of radioactivity after interrupted incubation with radiolabelled Affibody ligands. In vivo, the biodistribution of 125I-PIB-Z(HER2:342) was characterized by a high tumour uptake at 4 h pi (12.7+/-4.6% IA/g) and a quick clearance from blood and normal organs. The tumour uptake of 125I-DABI-Z(HER2:342) was appreciably lower (2.7+/-1.2% IA/g), and a high uptake of this conjugate in the liver was observed. A gamma-camera experiment (at 6 h pi) demonstrated that the use of 125I-PIB-Z(HER2:342) provided a much better contrast of imaging HER2-expressing xenografts than the use of 125I-DABI-Z(HER2:342). In conclusion, 125I-PIB-Z(HER2:342) is superior to 125I-DABI-Z(HER2:342) as an agent for imaging HER2 expression in vivo.
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| 13. |
- Wågsäter, Dick, et al.
(författare)
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All-trans retinoic acid regulates CXCL16/SR-PSOX expression
- 2005
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 16:4, s. 661-665
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have shown the ability of retinoids to modulate inflammatory response. CXCL16/SR-PSOX is a novel protein functioning as a chemokine and a scavenger receptor. We investigated effects of all-trans retinoic acid (atRA) on CXCL16/SR-PSOX expression in several cell types. Real-time PCR showed that atRA increased CXCL16/SRPSOX mRNA expression in THP-1 and endothelial cells, which corresponded to increased release of CXCL16 protein from the cells, measured by ELISA. In THP-1 cells this effect was reduced by retinoic acid receptor (RAR) antagonist, which indicates receptor-mediated inhibition. RAR-alpha and RAR-gamma agonists increased CXCL16 release, which suggests RAR-mediated effect of atRA, which is not selective for a particular RAR subtype. In smooth muscle cells, up-regulation of CXCL16 mRNA was observed only after 96 h of treatment, while protein expression did not change. These findings suggest that retinoid signaling might be a pathway modulating inflammatory response by regulating CXCL16 expression in a cell-specific manner.
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| 14. |
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| 15. |
- Buchwald, Pamela, et al.
(författare)
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Vitamin D in normal and pathological parathyroid glands: New prospects for treating hyperparathyroidism (Review)
- 2005
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Ingår i: International Journal of Molecular Medicine. - 1791-244X. ; 15:4, s. 701-706
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Forskningsöversikt (refereegranskat)abstract
- The secosteroid hormone active vitamin D [1,25(OH)(2)D-3] is a key player in the regulation of calcium homeostasis and bone mineralization. In addition, it has antiproliferative and prodifferentiating effects on various cells in vitro and in vivo. The action of 1,25(OH)(2)D-3 is mediated through the vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. VDR is expressed in the intestine, bone, kidney, parathyroid glands, and in many other tissues and cell types. In the parathyroid glands, 1,25(OH)(2)D-3 markedly decreases parathyroid hormone gene transcription and parathyroid cell proliferation and induces parathyroid cell differentiation. Diminished VDR expression is frequent in parathyroid tumors and probably contributes to parathyroid tumorigenesis. The enzyme responsible for catalyzing synthesis of 1,25(OH)(2)D-3 (1 alpha-hydroxylase) has lately been demonstrated in the parathyroid glands. This indicates a new role for 1 alpha-hydroxylase as an intracrine modulator of vitamin D function in non-renal tissues, which recently has been recognized as crucial in parathyroid tumor development. The growth-inhibitory properties of 1,25(OH)(2)D-3 are prospects for treatment of hyperparathyroidism.
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| 16. |
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| 17. |
- Ejeskär, Katarina, 1969, et al.
(författare)
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Method for efficient transfection of in vitro-transcribed mRNA into SK-N-AS and HEK293 cells: difference in the toxicity of nuclear EGFP compared to cytoplasmic EGFP.
- 2006
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Ingår i: International journal of molecular medicine. - 1107-3756. ; 17:6, s. 1011-6
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a method for efficient transfection of in vitro-transcribed mRNA into two different types of human adherent cells, the neuroblastoma cell line SK-N-AS, and the transformed kidney cell line HEK293. By using newly trypsinized adherent cells in suspension and Lipofectaminetrade mark 2000, we detected a transfection efficiency of 80-90% in both cell lines and a cell viability of 90% in SK-N-AS and 60% in HEK293, 24 h after transfection when using cytoplasmic enhanced green fluorescent protein (EGFP)-mRNA. We have evaluated the different effects of the generally used EGFP that mainly localizes to the cytoplasm and nuclear EGFP, where the nuclear EGFP are more toxic to the cells than the cytoplasmic EGFP. In order to develop a null experiment, we constructed a short non-functional mRNA including a nuclear localization signal and evaluated the concentrations at which mRNA encoding nuclear proteins can be added without a general toxicity, depending on the fact that the proteins are localized to the nucleus. For both SK-N-AS and HEK293 cells, a concentration of up to 100 ng mRNA in 10(5) cells, encoding a nuclear protein with no other function, did not affect the cells. For evaluation of the method, we screened four different human mRNAs, PDG, DFFA, CORT and PEX14, for their ability to affect cell proliferation in these cells. PEX14 was the only gene that significantly (p=0.03) reduced cell proliferation for both cell types, DFFA significantly (p=0.04) reduced cell proliferation in SK-N-AS but not in HEK293 cells. PGD and CORT did not have any effect on cell proliferation. We have developed an easy method for efficient delivery of in vitro-transcribed mRNA into the adherent cell lines, SK-N-AS and HEK293. This method is useful for a quick screening of how different genes affect cell proliferation.
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| 18. |
- Hägg, Daniel, 1974, et al.
(författare)
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Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
- 2008
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Ingår i: International journal of molecular medicine. - 1107-3756. ; 21:6, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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Urokinase-type plasminogen activator receptor is associated with macrophages and plaque rupture in symptomatic carotid atherosclerosis.
- 2008
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Ingår i: International journal of molecular medicine. - : Spandidos Publications. - 1107-3756. ; 22:4, s. 459-64
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Tidskriftsartikel (refereegranskat)abstract
- There is a strong correlation between macrophage infiltration and plaque instability in recently symptomatic carotid atherosclerotic plaques, and it is hypothesised that mechanisms related to macrophages may be involved in plaque vulnerability and rupture. We previously found high expression of urokinase-type plasminogen activator receptor (UPAR) in human macrophages. The aim of this study was to investigate whether UPAR co-localises with macrophages in symptomatic carotid plaques, and whether UPAR expression is associated with plaque rupture. Real-time RT-PCR assays showed that UPAR expression levels were high in monocyte-derived macrophages and in carotid endarterectomies compared with a tissue panel. Serial transverse sections were prepared from carotid endarterectomies from 12 symptomatic patients, and analyzed with immunohistochemical staining for UPAR and for CD68-positive macrophages, and with histopathological assessment. UPAR co-localised with CD68-positive macrophages, with a high correlation (r=0.90, p<0.001) between immunostained areas in 12 carotid endarterectomies from symptomatic patients. High degrees of UPAR and CD68 staining were found in sections around the bifurcation level where rupture was most common, while low degrees of staining were found in sections of the common carotid artery end of the endarterectomy (p<0.05). Higher degrees of UPAR staining were observed in ruptured plaque sections compared with non-ruptured sections. In conclusion, UPAR was highly expressed in monocyte-derived macrophages and in symptomatic carotid plaques, UPAR co-localised with macrophages in carotid symptomatic plaques and UPAR was predominantly found in ruptured plaque segments. These findings support the hypothesis that UPAR is related to plaque rupture in symptomatic atherosclerotic lesions.
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| 29. |
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