| 1. |
- Iglesias-Gato, Diego, et al.
(författare)
-
The Proteome of Primary Prostate Cancer
- 2016
-
Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 69:5, s. 942-952
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries.Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness.Design, setting, and participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker.Results and limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors.Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors.Patient summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
|
|
| 2. |
- Akhter, Tansim, 1967-, et al.
(författare)
-
Association between angiogenic factors and signs of arterial aging in women with pre-eclampsia
- 2017
-
Ingår i: Ultrasound in Obstetrics and Gynecology. - : Wiley. - 0960-7692 .- 1469-0705. ; 50, s. 93-99
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Pre-eclampsia (PE) is associated with an increased risk of cardiovascular disease (CVD) later in life. In PE there is a substantial increase in levels of the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt1) and decreased levels of the pro-angiogenic factor placental growth factor (PlGF). Elevated levels of sFlt1 are also found in individuals with CVD. The aims of this study were to assess sFlt1, PlGF and the sFlt1/PlGF ratio and their correlation with signs of arterial aging by measuring common carotid artery (CCA) intima and media thicknesses and their ratio (I/M ratio) in women with and without PE.METHODS: Serum sFlt1 and PlGF levels were measured using commercially available enzyme-linked immunosorbent assay kits, and CCA intima and media thicknesses were estimated using high-frequency (22 MHz) ultrasonography in 55 women at PE diagnosis and 64 women with normal pregnancies at a similar gestational age, with reassessment one year postpartum. A thick intima, thin media and a high I/M ratio indicate a less healthy arterial wall.RESULTS: During pregnancy, higher levels of sFlt1, lower levels of PlGF and thicker intima, thinner media and higher I/M ratios were found in women with PE vs. controls (all p < 0.0001). Further, sFlt1 and the sFlt1/PlGF ratio were positively correlated with intima thickness and I/M ratio (all p < 0.0001), but negatively correlated with media thickness (p = 0.002 and 0.03, respectively). About one year postpartum, levels of sFlt1 and the sFlt1/PlGF ratio had decreased in both groups, but compared with controls women in the PE group still had higher levels (p = 0.001 and 0.02, respectively). Further, sFlt1 levels and the sFlt1/PlGF ratio were still positively correlated with intima thickness and I/M ratio.CONCLUSIONS: Higher sFlt1 levels and sFlt1/PlGF ratios in women with PE were positively associated with signs of arterial aging during pregnancy. About one year postpartum sFlt1 levels and the sFlt1/PlGF ratios were still higher in the PE group, and also associated with the degree of arterial aging.
|
|
| 3. |
- Akhter, Tansim, 1967-, et al.
(författare)
-
Serum Pentraxin 3 is associated with signs of arterial alteration in women with preeclampsia.
- 2017
-
Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 241, s. 417-422
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Preeclampsia (PE) in pregnancy is a state of exaggerated inflammation and is associated with an increased risk of cardiovascular disease (CVD) later in life. Levels of pentraxin 3 (PTX3), a novel inflammation marker, are increased during PE and in individuals with CVD. The primary aim of this study was to assess whether serum PTX3 in women with PE is associated with adverse arterial effects; a thicker intima and higher intima/media (I/M) ratio in the common carotid artery (CCA).METHODS: Serum PTX3 levels were measured using commercially available enzyme-linked immunosorbent assay kits, and individual CCA intima and media thicknesses were estimated by 22MHz non-invasive ultrasound in 55 women at PE diagnosis and 64 women with normal pregnancies at a similar gestational age, and about one year postpartum. A thick intima, thin media and high I/M ratio indicate a less healthy artery wall.RESULTS: During pregnancy serum PTX3 correlated positively with intima thickness and I/M ratio but negatively with media thickness (all p<0.0001), indicating adverse arterial effects. About one year postpartum, PTX3 levels had decreased in both groups and there remained no significant group difference or significant correlation with CCA wall layers.CONCLUSIONS: Higher levels of serum PTX3 in women with PE were significantly associated with signs of adverse arterial effects during pregnancy, but not one year postpartum, supporting the rapid dynamics of PTX3.
|
|
| 4. |
- Bergman, Lina, et al.
(författare)
-
Preeclampsia and Increased Permeability Over the Blood–Brain Barrier : A Role of Vascular Endothelial Growth Receptor 2
- 2021
-
Ingår i: American Journal of Hypertension. - : Oxford University Press. - 0895-7061 .- 1941-7225. ; 34:1, s. 73-81
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebral complications in preeclampsia are leading causes of maternal mortality worldwide but the underlying pathophysiology is largely unknown and a challenge to study. Using an in vitro model of the human blood brain barrier (BBB), we explored the role of vascular endothelial growth factor receptor 2 (VEGFR2) in preeclampsia.METHODS: The human brain endothelial cell line (hCMEC/D3) cultured on Tranwells insert were exposed (12 h) to plasma from women with preeclampsia (n=28), normal pregnancy (n=28) and non-pregnant (n=16) controls. Transendothelial electrical resistance (TEER) and permeability to 70 kDa FITC-dextran were measured for assessment of BBB integrity. We explored possible underlying mechanisms, with focus on expression of tight junction proteins and phosphorylation of two tyrosine residues of VEGFR2, associated with vascular permeability and migration (pY951) and cell proliferation (pY1175). Plasma concentrations of soluble FMS like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured in order to establish correlations with in vitro results.RESULTS: hCMEC/D3 exposed to plasma from women with preeclampsia exhibited reduced TEER and increased permeability to 70 kDa FITC-dextran. Further, these cells up-regulated the mRNA levels of VEGFR2, as well as pY951-VEGFR2; but reduced pY1175-VEGFR2 (p&0.05 in all cases). No difference in mRNA expression of tight junction protein was observed between gruops. There was no correlation between angiogenic biomarkers and BBB permeability.CONCLUSION: We present a promising in vitro model of the BBB in preeclampsia. Selective tyrosine phosphorylation of VEGFR2 may participate in the increased BBB permeability in preeclampsia irrespective of plasma concentrations of angiogenic biomarkers.
|
|
| 5. |
- Bjerner, Tomas, et al.
(författare)
-
Evaluation of nonperfused myocardial ischemia with MRI and an intravascular USPIO contrast agent in an ex vivo pig model
- 2000
-
Ingår i: Journal of Magnetic Resonance Imaging. - 1053-1807 .- 1522-2586. ; 12:6, s. 866-872
-
Tidskriftsartikel (refereegranskat)abstract
- The ultrasmall superparamagnetic iron oxide (USPIO) preparation NC100150 Injection (Clariscan; Nycomed Imaging, Oslo, Norway) was tested for its ability to delineate nonperfused myocardium under steady-state conditions. An experimental animal model of focal myocardial ischemia induced by ligation of the distal part of the left anterior descending artery was used. The contrast agent was administered in four doses: 0, 4, 8, and 12 mg Fe/kg body weight. Magnetic resonance examination ex vivo, including T1-, T2-, and T2*-weighted sequences, was performed. Nonperfused myocardium was determined by fluorescein. The best delineation of nonperfused myocardium was found with a T1-weighted inversion recovery/turbo spin-echo sequence and doses of 4 and 8 mg Fe/kg body weight, where 95% of the volume was discernible at the dose of 4 mg Fe/kg body weight. The results suggest that steady-state imaging by T1-weighted sequence with the use of NC100150 Injection to delineate nonperfused myocardium is feasible. J. Magn. Reson. Imaging 2000;12:866-872.
|
|
| 6. |
- Bjerner, Tomas, et al.
(författare)
-
First-Pass Myocardial Perfusion MR Imaging with Outer-Volume Suppression and the Intravascular Contrast Agent NC100150 Injection : Preliminary Results in Eight Patients.
- 2001
-
Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 221:3, s. 822-826
-
Tidskriftsartikel (refereegranskat)abstract
- The authors evaluated the feasibility of combining single-shot T2-weighted turbo spin-echo magnetic resonance (MR) imaging and first-pass myocardial perfusion MR imaging with an intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agent, NC100150 Injection (3 mg of iron per kilogram of body weight). Eight patients with coronary vessel disease underwent T2-weighted turbo spin-echo MR imaging (in-plane resolution, 1-2 mm) during the first pass of the USPIO contrast agent. The mean decrease in signal intensity in myocardium perfused by a nonstenotic coronary artery was 59% +/- 13 (SD) (P < .012) This method is feasible for imaging of myocardial perfusion.
|
|
| 7. |
|
|
| 8. |
- Bojesson, Catarina
(författare)
-
Enabling Dynamic Capability : Managing and Organizing for Change
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis is based on a longitudinal single-case study conducted over five years within a product development context at a manufacturing company. In dynamic environments that demand flexibility and adaptability, it is essential to understand how organizations can improve dynamic capabilities to remain viable and competitive during periods of turbulence and change. This challenge is especially central to product development organizations offering customer-specific products as it tends to increase organizational complexity. An excessive focus on internal coordination and control to manage this complexity has led to inertia due to establishment of strict, rigid processes and hierarchical bureaucracies within organizational management and design.This study aims to contribute with new knowledge on how organizations operating in dynamic contexts can develop adaptability to changing needs. Specifically, it seeks to understand how to design and manage organizations to increase their preparedness for and adaptability to change. Investigating the factors and mechanisms that influence an organization's dynamic capability can provide insights into the sources of inertia and support the transition toward a more dynamic structure. The longitudinal study is based on data collected through an initial interview study followed by a questionnaire study, and finally through a concluding interview study. The research has been phenomenon-driven; as the organization’s circumstances have evolved, the focus of the study has shifted accordingly. Emerging from the aggregated results of the longitudinal study, the overall scope of the research is the change process, transitioning from a rigid to a more dynamic organization. Research findings are presented in five appended papers.Analysis from literature studies and the empirical study show that the primary focus on improving performance often centers on internal efficiency. However, within the case company, tension arose between the desire of strict control according to predefined processes and plans and the actual need for flexibility. Dynamic contexts require working processes that facilitate reactive problem-solving, creativity, and flexibility, as well as managers capable of going back and forth between management styles to benefit performance. Successful organizational reconfiguration depends on developing the conditions that enable the firm's dynamic capability in relation to its context. This involves identifying both the microfoundations that generate dynamic capability and the internal and external constraints to change.Considering the external environment is crucial for developing an understanding of how to best organize and manage resources and capabilities, which places demands on managerial capabilities. Managers must possess the skills to monitor the external environment and formulate strategies to respond to changing conditions, as their interpretation of the external environment will influence their decisions, which will subsequently enable or hinder possible actions. The design of organizations will impact the ability to rearrange resources and capabilities. Processes and working procedures must allow for reconfigurations to respond swiftly to changing constraints or opportunities. The use of multiple theoretical perspectives has been imperative in the analysis of the data, and the theoretical contribution extends to exploration of various factors and mechanisms that influence an organization's dynamic capability.
|
|
| 9. |
- Bovinder Ylitalo, Erik, et al.
(författare)
-
A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer
- 2021
-
Ingår i: Clinical Epigenetics. - : BioMed Central. - 1868-7083 .- 1868-7075. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.Materials and methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.
|
|
| 10. |
|
|
