| 1. |
- Botling, Johan, et al.
(författare)
-
Biomarker Discovery in Non-Small Cell Lung Cancer : Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation
- 2013
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 194-204
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.
|
|
| 2. |
- Holleboom, Adriaan G, et al.
(författare)
-
Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
- 2011
-
Ingår i: Cell Metabolism. - : Elsevier. - 1550-4131 .- 1932-7420. ; 14:6, s. 811-8
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
|
|
| 3. |
|
|
| 4. |
- Dreifaldt, Mats, 1959-
(författare)
-
Conduits in coronary artery bypass grafting surgery : Saphenous vein, radial and internal thoracic arteries
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A novel technique for saphenous vein (SV) graft harvesting, the No-touch technique (NT), has been developed at the Dept. of Cardiovascular surgery, Örebro University hospital. With NT the SV is harvested with a pedicle of surrounding tissue. This avoids graft spasm and eliminates the need for distension. The surrounding tissue acts as a structural support and is a rich source of vaso-dilating agents. A randomized controlled trial (RCT) has shown a significantly higher patency rate for NT SV grafts compared to SV grafts harvested with conventional technique (CT). This thesis evaluates some of the properties of the surrounding tissue and compares patency rates between NT SV and radial artery (RA) grafts and patency rates for internal thoracic artery (ITA) grafts harvested with and without surrounding tissue. Paper I investigated vasa vasorum (VV) in SV grafts and showed that the NT preserves an intact VV whereas CT does not. This could be one of the mechanisms underlying the improved patency for NT SV grafts. Paper II evaluated VV and associated nitric oxide (NO) in SV and arterial grafts. SV grafts showed a higher number and larger VV, which correlated with NO production, compared to arterial grafts. NT SV grafts showed higher activity for e-NOS compared to CT SV grafts. Paper III is a RCT comparing patency rates between NT SV and RA grafts, three years after surgery, showing a significantly higher patency rate for NT SV grafts. Paper IV is a RCT comparing patency rates for ITA graft harvested with and without surrounding tissue and did not show any difference between graft preparations. In conclusion, the NT for SV graft harvesting preserves an intact vasa vasorum and associated NO production. NT SV grafts show a higher patency rate than RA grafts. Harvesting of ITA with or without surrounding tissue does not affect patency rate.
|
|
| 5. |
- Dreifaldt, Mats, et al.
(författare)
-
The ‘‘no-touch’’ harvesting technique for vein grafts in coronary artery bypass surgery preserves an intact vasa vasorum
- 2011
-
Ingår i: The Internet Journal of Thoracic and Cardiovascular Surgery. - New York, USA : Elsevier. - 1524-0274 .- 0022-5223. ; 141:1, s. 145-150
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Our objective was to evaluate the impact of vein graft harvesting technique on structure and function of vasa vasorum.Methods: Paired segments of great saphenous veins harvested either with conventional harvesting technique or no-touch technique were obtained from 9 consecutive patients undergoing coronary artery bypass grafting. Quantitative measurements, using immunohistochemistry and morphometry, were performed. Ultrastructural analyses of vasa vasorum were performed with electron microscopy. Video footage of superficial vasa vasorum in an implanted saphenous vein graft harvested with the no-touch technique was captured during a coronary bypass operation and is presented for online viewing.Results: The total area of vasa vasorum in vein grafts harvested with the conventional technique was significantly reduced both in the media (P¼.007) and in the adventitia (P¼.014) compared with vein grafts harvested with the no-touch technique. Ultrastructural findings indicated that the no-touch technique preserved an intact vasa vasorum whereas the conventional technique did not. Video footage showed retrograde flow in the vasa vasorum in vein graft harvested with the no-touch technique.Conclusions: These findings showthat the no-touch technique for saphenous vein graft harvesting for coronary bypass grafting preserves an intact vasa vasorum. This could represent one of the mechanisms underlying the improved patency of saphenous vein grafts harvested with this technique.
|
|
| 6. |
- Falck, Eva, et al.
(författare)
-
Loss of Glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma
- 2010
-
Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.
|
|
| 7. |
- Karlsson, Christina, et al.
(författare)
-
Effects of long-term storage on the detection of proteins, DNA, and mRNA in tissue microarray slides
- 2011
-
Ingår i: Journal of Histochemistry and Cytochemistry. - : Sage Publications. - 0022-1554 .- 1551-5044. ; 59:12, s. 1113-1121
-
Tidskriftsartikel (refereegranskat)abstract
- Storage of tissue slides has been claimed to induce dramatically reduced antigen detection particularly for immunohistochemistry (IHC). With tissue microarrays, the necessity to serially cut blocks in order to obtain as much material as possible is obvious. The presumed adverse effect of storage might hamper such an approach. The authors designed an experimental setting consisting of four different storage conditions with storage time of tissue slides of up to 1 year. Detection of proteins, DNA, and mRNA was performed using IHC and in situ hybridization techniques. Slight but significant changes in IHC occurred over time. The most important factor is the primary antibody used: four showed no significant changes, whereas limited decreases in 8 antibodies could be detected by image analysis. Whether the antigen was nuclear or cytoplasmic/membranous did not matter. No major differences between different storage conditions could be shown, but storage at 4C was overall the best procedure. Furthermore, gene copy number aberrations, chromosomal translocations, and the presence of mRNA could be detected on slides stored up to 1 year. In conclusion, in tissues optimally formalin fixed and using modern histological techniques, only minute changes in tissue antigenicity are induced by long-term storage.
|
|
| 8. |
- Karlsson, Christina, 1968-, et al.
(författare)
-
Oestrogen receptor ss in NSCLC : prevalence, proliferative influence, prognostic impact and smoking
- 2012
-
Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Malden, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 120:6, s. 451-458
-
Tidskriftsartikel (refereegranskat)abstract
- In non-small-cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for oestrogen receptor (ER) signalling has been proposed. The role for ER beta in NSCLC is still not clear, especially concerning the impact of smoking. In a material of NSCLC (n = 262), ER beta and cyclins A1 and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ER beta) and cyclin A1 were performed. Data were correlated to histology, gender, smoking habits, stage and clinical outcome. ER beta was expressed in 86% of the cases. ER beta was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ER beta expression and cyclins was observed in ADCA, also with a male predominance. ER beta transcripts had a positive prognostic impact in ADCA. ER beta transcripts were increased in NSCLC among smokers compared to non-smokers. In conclusion, our data support a role for ER beta in lung ADCAs, proposing a role for ER beta in lungcarcinogenesis, especially among smokers.
|
|
| 9. |
- Karlsson, Helen, et al.
(författare)
-
Wear Particles from Studded Tires and Granite Pavement Induce Pro-inflammatory Alterations in Human Monocyte-Derived Macrophages : A Proteomic Study.
- 2011
-
Ingår i: Chemical Research in Toxicology. - : American Chemical Society. - 0893-228X .- 1520-5010. ; 24, s. 45-53
-
Tidskriftsartikel (refereegranskat)abstract
- Airborne particulate matter is considered to be one of the environmental contributors to the mortality in cancer, respiratory, and cardiovascular diseases. For future preventive actions, it is of major concern to investigate the toxicity of defined groups of airborne particles and to clarify their pathways in biological tissues. To expand the knowledge beyond general inflammatory markers, this study examined the toxicoproteomic effects on human monocyte derived macrophages after exposure to wear particles generated from the interface of studded tires and a granite-containing pavement. As comparison, the effect of endotoxin was also investigated. The macrophage proteome was separated using two-dimensional gel electrophoresis. Detected proteins were quantified, and selected proteins were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Among analyzed proteins, seven were significantly decreased and three were increased by exposure to wear particles as compared to unexposed control cells. Endotoxin exposure resulted in significant changes in the expression of six proteins: four decreased and two increased. For example, macrophage capping protein was significantly increased after wear particle exposure only, whereas calgizzarin and galectin-3 were increased by both wear particle and endotoxin exposure. Overall, proteins associated with inflammatory response were increased and proteins involved in cellular functions such as redox balance, anti-inflammatory response, and glycolysis were decreased. Investigating the effects of characterized wear particles on human macrophages with a toxicoproteomic approach has shown to be useful in the search for more detailed information about specific pathways and possible biological markers.
|
|
| 10. |
- Spetz, Anna-Clara, et al.
(författare)
-
Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism
- 2011
-
Ingår i: The Aging Male. - : Informa Healthcare. - 1368-5538 .- 1473-0790. ; 14:4, s. 249-256
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Symptoms of late-onset hypogonadism (LOH) and concentrations of testosterone (T) and bioavailable testosterone (BT) were studied in relation to the data from the same men 5 years earlier. less thanbrgreater than less thanbrgreater thanMethods. In 2008, 282 men, aged 60-82 years, answered a questionnaire regarding demographic data, medical history, different symptoms of LOH and the 10 questions from the Androgen Decline in Aging Males (ADAM)-questionnaire. Blood samples were analysed for concentrations of T and calculations were made for BT. less thanbrgreater than less thanbrgreater thanResults. A total of 87.2% of the questionnaires were returned and analysed, and 75.2% of the responders gave blood samples. The oldest third of the men were most affected by LOH symptoms (p andlt; 0.05). Both T and BT concentrations decreased during the 5 years (p andlt; 0.05) but only the symptom less strong erections changed significantly (p andlt; 0.05). Men reporting one of the four specific symptoms from the ADAM-questionnaire for the first time in 2008 had a higher loss of T and BT than men who had unchanged or fewer symptoms than that reported in 2003. less thanbrgreater than less thanbrgreater thanConclusions. The magnitude of the decrease in concentrations is a better predictor of LOH than are the actual concentrations of T and BT. A combination of symptoms predicts LOH better than any single symptom.
|
|
