| 1. |
- Mark, Andreas, 1980, et al.
(author)
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Microstructure Simulation of Early Paper Forming Using Immersed Boundary Methods
- 2011
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In: Paper360. - 1933-3684. ; 10:11, s. 23-30
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Journal article (peer-reviewed)abstract
- Paper forming is the first step in the paper machine where a fibersuspension leaves the headbox and flows through a forming fabric.Complex physical phenomena occur during paper forming due to theinteraction between fibers, fillers and fines as well as chemicalsadded to the suspension. Understanding this process is important forthe development of improved paper products because the configurationof the fibers during this step has a large influence on the finalpaper quality. Since the effective paper properties depend on themicro-structure of the fiber web, a continuum model is inadequate andthe properties of each fiber need to be accounted for in thesimulations.In the present work, a framework for microstructure simulation ofearly paper forming has been developed. The simulation frameworkincludes a Navier-Stokes solver and immersed boundary methods are usedto resolve the flow around the fibers. The fibers are modeled with afinite element discretization of the Euler-Bernoulli beam equation ina co-rotational formulation. The contact model is based on a penaltymethod and includes friction as well as elastic and inelasticcollisions.The fiber model and the contact model are validated against demandingtest cases from the literature with excellent results. Thefluid-structure interaction in the model is examined by simulating anelastic beam oscillating in a cross flow. Finally, a simulation ofearly paper forming is performed to demonstrate the potential of theproposed framework. The unique modeling approach can be used toincrease the fundamental understanding of paper forming and supportprocess optimization.
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| 2. |
- Mark, Andreas, 1980, et al.
(author)
-
Microstructure Simulation of Early Paper Forming Using Immersed Boundary Methods
- 2011
-
In: Progress in Paper Physics Seminar. - 9783851251630 ; , s. 283-290
-
Conference paper (peer-reviewed)abstract
- Paper forming is the first step in the paper machinewhere a fiber suspension leaves the headbox and flowsthrough a forming fabric. Understanding this processis important for the development of improved paperproducts because the configuration of the fibers duringthis step has a large influence on the final paperquality.The simulation framework includes IBOFlow, a stateof-the-art Navier-Stokes solver, and PaperGeo, the virtualpaper structure generator in GeoDict. ImmersedBoundary Methods are used to resolve the flow aroundthe fibers. The fibers are modeled with a finite elementdiscretization of the Euler-Bernoulli beam equationin a co-rotational formulation. The contact modelis based on a penalty method and includes friction aswell as elastic and inelastic collisions.The fiber model and the contact model are validatedagainst demanding test problems from the literaturewith excellent result. The fluid-structure interaction inthe model is examined by simulating an elastic beamoscillating in a cross flow. Finally, a simulation of initialpaper forming is performed, which demonstratesthe capabilities of the simulation framework.
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| 3. |
- Svenning, Erik, 1986, et al.
(author)
-
Multiphase Simulation of Fiber Suspension Flows Using Immersed Boundary Methods
- 2012
-
In: Nordic Pulp and Paper Research Journal. - 2000-0669 .- 0283-2631. ; 27:2, s. 184-191
-
Journal article (peer-reviewed)abstract
- Fiber suspension simulations are challenging since they involve transient fluid flow with immersed solid objects subject to large displacements and rotations. In the present work, a beam model in co-rotational formulation is coupled with a fluid solver using immersed boundary methods. The model is used to simulate a fiber in a shear flow and excellent agreement is found with Jeffery's equations. The shapes of fibers deforming in a shear flow are found to be in qualitative agreement with shapes observed in experiments.The flow of a fiber suspension is studied by simulating early paper forming with one-way and semi-two-way coupling. It is found that the flow through the fiber web needs to be resolved in order to predict the retention of fibers in the fiber web.
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| 4. |
- Andrä, Heiko, et al.
(author)
-
Micromechanical network model for the evaluation of quality controls of paper
- 2011
-
In: Progress in Paper Physics Seminar. - 9783851251630 ; , s. 49-55
-
Conference paper (peer-reviewed)abstract
- In this paper, we discuss the challenges in modelling and simulating infinitesimal and large deformations of cellulose fiber networks, mainly in the context of the prediction of quality controls for paper.Understanding the influence and sensitivity of macroscopic production parameters like grammage and thickness of paperboard and understanding the influence of the fiber suspension on the quality of paper is important for the development of better papers and for preserving raw materials and energy.The new simulation framework consists of the virtual stochastic paper structure generator PaperGeo, that was integrated in the GeoDict 1 software suite, and the finite element solver FeelMath (Finite Elements for Elastic Materials and Homogenization) for solving the equations of elasticity. The fibers and the contacts are modelled by using geometrically exact beams of Simo-type [1].The microstructural model and the fiber network model are validated against standard measurements of existing papers in the following way: At first we perform tensile and bending tests to measure the macroscopic stress-strain relations. In the next step we apply a representative macroscopic stress or strain onto the boundaries of realizations of the stochastic fiber network model and compute by homogenization the effective (stiffness) coefficients. Finally we compare the numerical results with the measurements.This procedure can also be used for an identification of elastic parameters on the microscale and to study the sensitivity of the effective (macroscopic) stiffness with regard to the parameters of the microstructure
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| 5. |
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| 6. |
- Brüggemann, Anders, et al.
(author)
-
Are porous tantalum cups superior to conventional reinforcement rings? : A retrospective cohort study of 207 acetabular revisions
- 2017
-
In: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 88:1, s. 35-40
-
Journal article (peer-reviewed)abstract
- Background and purpose - Porous tantalum cups have been introduced as an alternative to various reinforcement rings in revision hip surgery. We hypothesized that porous tantalum cups would be superior to muller acetabular roof reinforcement rings (MARRs) in revision hip surgery with re-revision for aseptic loosening as the primary outcome measure. Patients and methods - 207 hips operated with either a porous tantalum cup (TM cup, n = 111) or a MARR (n = 96) at index procedure were identified in our local arthroplasty register. Acetabular defects were classified according to Paprosky. There were 96 men and 111 women with a median age of 71 (35-95) years, presenting acetabular defect size type I in 39 cases, IIA in 22, IIB in 27, IIC in 43, IIIA in 32, and IIIB in 37 cases. Analysis of medical records identified all patients with subsequent re-revision and reasons for re-revisions. Kaplan-Meier survival functions were used to estimate implant survival. Results - With re-revision for aseptic loosening as the end-point, the 6-year unadjusted cumulative survival was 97% (95% CI: 94-100) for TM cups and 96% (CI: 92-100) for MARR (p = 0.6). Using re-revision for any reason as the endpoint, 6-year survival was 87% (CI: 81-94) for TM cups and 95% (CI: 90-99) for MARR (p = 0.06). The main reason for re-revision in the TM group was dislocation (n = 10), followed by loosening (n = 3), whereas the main reason for re-revision in the MARR group was aseptic loosening (n = 8). Duration of the index procedure and perioperative blood loss were lower in the TM group. Interpretation - Both TM and MARR lead to good 6-year results in acetabular revision surgery. The methods differ in their respective failure mechanisms. We conclude that TM cups are a valuable treatment option in acetabular revision surgery, but the reasons underlying dislocations after the use of TM cups must be analyzed further.
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| 7. |
- Cifani, Paolo, et al.
(author)
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Hunting for Protein Markers of Hypoxia by Combining Plasma Membrane Enrichment with a New Approach to Membrane Protein Analysis
- 2011
-
In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 10:4, s. 1645-1656
-
Journal article (peer-reviewed)abstract
- Nontransient hypoxia is strongly associated with malignant lesions, resulting in aggressive behavior and resistance to treatment. We present an analysis of mRNA and protein expression changes in neuroblastoma cell lines occurring upon the transition from normoxia to hypoxia. The correlation between mRNA and protein level changes was poor, although some known hypoxia-driven genes and proteins correlated well. We present previously undescribed membrane proteins expressed under hypoxic conditions that are candidates for evaluation as biomarkers.
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| 8. |
- Cirenajwis, Helena, et al.
(author)
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Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
-
In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
-
Journal article (peer-reviewed)abstract
- Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
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| 9. |
- Fang, Hsin-Yu, et al.
(author)
-
Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia
- 2009
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 114:4, s. 844-859
-
Journal article (peer-reviewed)abstract
- Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1 beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappa B (NF-kappa B) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1 alpha and 2 alpha or NF-kappa B in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappa B, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors. (Blood. 2009; 114: 844-859)
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| 10. |
- Fredlund, Erik, et al.
(author)
-
High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma.
- 2008
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 105:37, s. 14094-14099
-
Journal article (peer-reviewed)abstract
- The childhood cancer neuroblastoma arises in the developing sympathetic nervous system and is a genotypically and phenotypically heterogeneous disease. Prognostic markers of poor survival probability include amplification of the MYCN oncogene and an undifferentiated morphology. Whereas these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. In this study, we analyze two large neuroblastoma microarray datasets using a priori-defined gene expression signatures. We show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predicts relapse and death from disease. This was evident not only for high-risk patients but was also robust in identifying groups of poor prognosis patients who were otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma.
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| 11. |
- Fredlund, Erik
(author)
-
Hypoxic gene regulation and oncogenic pathways in neuroblastoma
- 2008
-
Doctoral thesis (other academic/artistic)abstract
- Neuroblastoma patients show remarkable clinical heterogeneity, with courses ranging from spontaneous regression to fatal tumor progression despite intense multi-modal treatment. Previous studies have shown that hypoxia pushes neuroblastoma cells towards a more immature phenotype, which correlates to aggressive disease. Here we define a role for the hypoxia inducible factor-2α in neuroblastoma tumor progression. While HIF-1α was transiently stabilized at hypoxia (1% oxygen), HIF-2α was induced and regulated HIF-specific target genes, such as VEGF, at later time points. Furthermore, HIF-2α was stabilized and transcriptionally active in cells grown at physiological oxygen levels (5% O2). Subsequent microarray analysis showed that HIF-2α induced genes, previously identified as hypoxia regulated, at this physiological oxygen level. Several of these genes have been implicated in tumorigenic processes and correlated to adverse patient outcome in various tumor forms. Indeed, siRNA mediated knock-down of HIF-2α in neuroblastoma cells significantly reduced xenograft tumor growth, as compared to siHIF1-α treated or wild-type cells. Moreover, immunohistochemical analyses of a large neuroblastoma tumor material arranged in a tissue microarray showed that HIF-2α expression correlated to VEGF, and that high HIF-2α levels was predictive of poor patient prognosis. Prognostic markers of neuroblastoma patient adverse prognosis include amplification of the MYCN oncogene and an undifferentiated morphology. While these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. We analyze two large neuroblastoma microarray data sets by using a priori-defined gene expression signatures. The results show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predict relapse and death from disease. This was evident not only for high-risk patients, but also was robust in identifying groups of poor prognosis patients otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma.
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| 12. |
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| 13. |
- Fredlund, Erik, et al.
(author)
-
The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial-mesenchymal transition
- 2012
-
In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 14:4
-
Journal article (peer-reviewed)abstract
- Introduction: Gene expression data derived from clinical cancer specimens provide an opportunity to characterize cancer-specific transcriptional programs. Here, we present an analysis delineating a correlation-based gene expression landscape of breast cancer that identifies modules with strong associations to breast cancer-specific and general tumor biology. Methods: Modules of highly connected genes were extracted from a gene co-expression network that was constructed based on Pearson correlation, and module activities were then calculated using a pathway activity score. Functional annotations of modules were experimentally validated with an siRNA cell spot microarray system using the KPL-4 breast cancer cell line, and by using gene expression data from functional studies. Modules were derived using gene expression data representing 1,608 breast cancer samples and validated in data sets representing 971 independent breast cancer samples as well as 1,231 samples from other cancer forms. Results: The initial co-expression network analysis resulted in the characterization of eight tightly regulated gene modules. Cell cycle genes were divided into two transcriptional programs, and experimental validation using an siRNA screen showed different functional roles for these programs during proliferation. The division of the two programs was found to act as a marker for tumor protein p53 (TP53) gene status in luminal breast cancer, with the two programs being separated only in luminal tumors with functional p53 (encoded by TP53). Moreover, a module containing fibroblast and stroma-related genes was highly expressed in fibroblasts, but was also up-regulated by overexpression of epithelial-mesenchymal transition factors such as transforming growth factor beta 1 (TGF-beta1) and Snail in immortalized human mammary epithelial cells. Strikingly, the stroma transcriptional program related to less malignant tumors for luminal disease and aggressive lymph node positive disease among basal-like tumors. Conclusions: We have derived a robust gene expression landscape of breast cancer that reflects known subtypes as well as heterogeneity within these subtypes. By applying the modules to TP53-mutated samples we shed light on the biological consequences of non-functional p53 in otherwise low-proliferating luminal breast cancer. Furthermore, as in the case of the stroma module, we show that the biological and clinical interpretation of a set of co-regulated genes is subtype-dependent.
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| 14. |
- Fredlund, Erik, et al.
(author)
-
Transcriptional adaptation of neuroblastoma cells to hypoxia.
- 2008
-
In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 366:4, s. 1054-1060
-
Journal article (peer-reviewed)abstract
- Low oxygen pressure (hypoxia) is a physiological condition that has been linked to tumor progression and increased malignancy in several cancer forms. Cells of the childhood neoplasm neuroblastoma respond to hypoxia by attaining a lower grade of differentiation, which clinically is associated with poor prognosis. Furthermore, expression of the hypoxia inducible factor-2alpha correlates to poor outcome in neuroblastoma patients. In this report we have by microarray analysis studied transcriptional changes in seven neuroblastoma cell lines subjected to long term hypoxia. We find the gene regulatory response to be highly dependent on cell line background, however, a set of genes was coherently regulated by hypoxia and these genes are correlated to known hypoxia-induced transcriptional profiles.
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| 15. |
- Fredlund, Tobias, et al.
(author)
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Analysing school science group work in terms of multimodal text development and its interplay with the context of situation
- 2018
-
In: 9ICOM Book of Abstracts. ; , s. 64-64
-
Conference paper (other academic/artistic)abstract
- Social semiotics terms the immediate environment in which a text functions the ‘context of situation’ – an instance of the context of culture. The context of situation is defined by three parameters, FIELD, TENOR and MODE, which can be operationalized by the WHAT, the WHO and the HOW of a text functioning in a science classroom (Knain, 2015). Text and context mutually enable and constrain each other in acts of meaning. For something to be a text, it must both hang together internally and cohere externally in terms of the three contextual parameters (Halliday & Hasan, 2013). In this paper, we argue that although group work in science classes can be seen as joint text development, what is actually developed is often not a text, but a trajectory of different multimodal texts, each with its own text-context relationship. This is because the students sometimes jump between different topics, which point to different values of the context-parameters. We present an analysis of video recorded student group work where the students produce a trajectory of multimodal texts and move between different contexts of situation – as judged by the values of the contextual parameters. But there is one main thread that they continuously return to. This thread is both internally cohesive and coherent with a (developing) context of situation, and thus constitutes a text. Our analyses suggest that a factor that helps in enabling the students to return to this main thread is a drawing that they produce. A number of aspects of visual grammar are used as indications of the continuous transformation of both the text and its context of situation, including framing, foregrounding and backgrounding. We suggest that this process of multimodal text development is likely to be characteristic for learning trajectories
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| 16. |
- Fredlund, Tobias, et al.
(author)
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Science students' noticing of appropriate frames
- 2019
-
Conference paper (peer-reviewed)abstract
- In this theoretical paper we draw on two constructs that we argue are related to the appropriate interpretation of many representations in science education: frames and structures of awareness. By representations is meant, for example, images, diagrams and models. The idea of frames is taken from social semiotics and the idea of structures of awareness is taken from the variation theory of learning. Using both an everyday example and examples from science education we make the argument that students need to become explicitly aware of tacitly held structures of awareness that frame their interpretation of representations. A task for science educators would be to investigate the possibility to produce representations that could aid students in this work.
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| 17. |
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| 18. |
- Fredlund, Tobias, et al.
(author)
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The epistemological commitments of modes : Opportunities and challenges for science learning
- 2024
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In: Visual Communication. - : Sage. - 1470-3572 .- 1741-3214. ; 23:1, s. 97-118
-
Journal article (peer-reviewed)abstract
- Meaning making in science is supported by different modes, such as spoken and written language, images and gestures, all of which have different affordances. The epistemological commitments of modes are affordances that cannot be avoided. This article investigates how the epistemological commitments of modes affect possibilities for learning. Video data was collected from a learning activity where upper secondary students drew and explained an experiment representing the greenhouse effect. The analysis uses the variation theory of learning, which assumes that students learn when they notice new aspects of objects of learning by experiencing variation against an invariant background. Such variation can be created through the representations used. Findings show that, in the learning activity, variation was created in a range of modes. Some of the variation, particularly with regards to radiation, was due to the epistemological commitments of drawing. However, these aspects of radiation went unnoticed by the students, possibly because several aspects varied simultaneously. The teacher then helped the students to become aware of certain variation. Implications for the teaching and learning of science when taking the epistemological commitment of different modes into consideration include both challenges, such as when unintended variation is created, and opportunities, such as when spontaneously occurring variation can be taken up for discussion.
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| 19. |
- Fredlund, Tobias, et al.
(author)
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The transition from naturalistic to theoretical representations of the greenhouse effect
- 2017
-
Conference paper (other academic/artistic)abstract
- The paper reports on a study of students' interactions and transformations of various forms of representations, textual and visual, related to the concept of the greenhouse effect. Competent participation in representational practices is at the heart of scientific literacy and several studies have documented positive effects of introducing students to complex scientific concepts such as the greenhouse effect by means of engaging with various forms of representations. However, studies also show that even though the topic is related to everyday experience (weather, light, heat), the concept of the greenhouse effect is challenging for students. This is partly because of its many invisible processes, such as the transformation of sunlight into heat radiation and its absorption by greenhouse gases. This paper extends previous knowledge by showing how students' representations develop from naturalistic depiction to scientific abstraction. In particular, it shows how the students' framing, foregrounding and backgrounding relate various naturalistic and scientific aspects in their drawings; connect multiple modes of representation and their affordances in peer and teacher negotiations; and how this enables sustained inquiry. Implications for teaching and learning are discussed.
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| 20. |
- Fredlund, Tobias, et al.
(author)
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Two central aspects of sign-making for the learning of science : differentiation and integration
- 2017
-
Conference paper (other academic/artistic)abstract
- In this theoretical paper, we explore the role that sign-making practices such as differentiation into parts and integration of parts play for successful student learning in science. Taking a social semiotic stance, we view student interest, such as their judgement of what is relevant and appropriate for the situation at hand and of who is the ‘reader’ of the sign, as the basis for their sign-making. Thus, sign making includes judgements of what to say, how to say it, and by what means to say it – viz. speech, writing, drawing, etc. Our explorative investigation is guided by a multimodal approach to sensemaking, and our analyses are illustrated with excerpts from classroom video data collected when first year upper secondary school students attempt to explain an experimental model of the greenhouse effect. The implications for teaching and learning include that in order to enhance student learning in science, learning tasks need to be created that engage students and prompt their sign-making. By supporting students in focusing on differentiation and integration of parts, students get the tools they need to develop their way of knowing. Thus teachers should pay close attention to students’ sign-making and how it can be supported.
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| 21. |
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| 22. |
- Helczynska, Karolina, et al.
(author)
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Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
- 2008
-
In: Cancer Research. - 1538-7445. ; 68:22, s. 9212-9220
-
Journal article (peer-reviewed)abstract
- Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.
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| 23. |
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| 24. |
- Johansson, Henrik J., et al.
(author)
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Breast cancer quantitative proteome and proteogenomic landscape
- 2019
-
In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
-
Journal article (peer-reviewed)abstract
- In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
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| 25. |
- Jurstrand, Margaretha, 1947-
(author)
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Detection of Chlamydia trachomatis and Mycoplasma genitalium by genetic and serological methods
- 2006
-
Doctoral thesis (other academic/artistic)abstract
- Chlamydia trachomatis infections are associated with a spectrum of clinical diseases including urethritis, prostatitis and epididymitis among men and cervicitis and pelvic inflammatory disease (PID), with an increased risk of infertility and ectopic pregnancy (EP), among women. In the search for other pathogens causing urethritis, Mycoplasma genitalium was isolated from urethral specimens from two men with acute urethritis (1980). Mycoplasma bacteria are extremely difficult to isolate by culture, and clinical studies have been possible only after the advent of the first PCR-based detection method. M. genitalium has been found to be associated with lower genital tract infections in both men and women. Finding evidence for a connection between M. genitalium and upper genital tract infections in women is still of major importance. The aim in papers I and II was to develop a PCR method for genetic characterization of clinical C. trachomatis isolates by sequence analysis of the omp1 gene, and to study the distribution of genotypes within sexual networks and determine if genotyping would improve partner notification. The method was used to determine the genotypes of C. trachomatis in 237 positive urogenital and/or urine specimens from men and women attending the STDClinic in Örebro during one year. Sequence analysis of the omp1 gene revealed that the most prevalent genotypes corresponded to C. trachomatis serovar E (47%), followed by F (17%), and K (9%). There were 161 networks found and specimens were sequenced from at least two patients in 47 networks. In seven of these 47 networks there were discrepant genotypes. In the largest network comprising 26 individuals two different C. trachomatis genotypes were found, and one partner had urethritis due to a Mycoplasma genitalium infection but was C. trachomatis negative. The need for a new method for M. genitalium DNA detection was one reason for study III. An existing conventional PCR protocol for detection of M. genitalium DNA was further developed into a real-time PCR (RT-PCR) with hybridisation probes. In order to evaluate the RT-PCR assay with clinical material, specimens from 398 men and 301 women attending the STD Clinic in Örebro were analysed, using the RT-PCR assay, and also by the well established conventional PCR in Copenhagen. Using the conventional PCR method as “gold standard”, the sensitivity for the RT-PCR assay was 72.2% and 68.2% and the specificity was 99.7% and 98.6%, respectively, in urogenital specimens from men and women. The aim in paper IV was to adapt a Triton X-114 extracted Lipid-Associated Membrane Protein (LAMP) Enzyme Immuno Assays (EIA) method to detect antibodies against M. genitalium and to evaluate the association between M. genitalium and PID and EP, using sera sampled in Örebro during the 1980s, and also to compare the number of sera having M. genitalium antibodies against those having C. trachomatis antibodies, using a commercial anti- Chlamydia trachomatis EIA assay. No statistical significant association could be demonstrated between M. genitalium antibodies and PID or EP in our serum material. However, a slight trend toward association was found when focusing on younger individuals. Antibodies against C. trachomatis were found to be significantly associated with PID and EP.
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| 26. |
- Kasza, Z., et al.
(author)
-
MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA)
- 2013
-
In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:36, s. 25956-25963
-
Journal article (peer-reviewed)abstract
- Heparan sulfate (HS) proteoglycans, present at the plasma membrane of vascular endothelial cells, bind to the angiogenic growth factor VEGFA to modulate its signaling through VEGFR2. The interactions between VEGFA and proteoglycan co-receptors require sulfated domains in the HS chains. To date, it is essentially unknown how the formation of sulfated protein-binding domains in HS can be regulated by microRNAs. In the present study, we show that microRNA-24 (miR-24) targets NDST1 to reduce HS sulfation and thereby the binding affinity of HS for VEGFA. Elevated levels of miR-24 also resulted in reduced levels of VEGFR2 and blunted VEGFA signaling. Similarly, suppression of NDST1 using siRNA led to a reduction in VEGFR2 expression. Consequently, not only VEGFA binding, but also VEGFR2 protein expression is dependent on NDST1 function. Furthermore, overexpression of miR-24, or siRNA-mediated reduction of NDST1, reduced endothelial cell chemotaxis in response to VEGFA. These findings establish NDST1 as a target of miR-24 and demonstrate how such NDST1 suppression in endothelial cells results in reduced responsiveness to VEGFA.
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| 27. |
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| 28. |
- Knain, Erik, et al.
(author)
-
Exploring Student Reasoning and Representation Construction in School Science Through the Lenses of Social Semiotics and Interaction Analysis
- 2021
-
In: Research in science education. - : Springer. - 0157-244X .- 1573-1898. ; 51:1, s. 93-111
-
Journal article (peer-reviewed)abstract
- The meaning-making practices of science are multimodal and include representational forms such as spoken and written language, diagrams, graphs, equations, and images. Science learning proceeds through an ever-increasing grasp of such resources. This study aims at providing insight into how a combination of Interaction Analysis (IA) and social semiotic analysis can provide a deeper understanding of students’ engagement and learning with science representations. Social semiotics offers an analytical lens and categories for interpreting nuances of meaning in the visual domain. IA places a strong methodological emphasis on grounding analysis in unfolding interactions among peers, teachers, and artefacts. Investigating a teaching design where students iteratively produce multimodal drawings of the greenhouse effect, we used a multimodal analysis of the students’ drawings and an IA of transcribed video recordings of students’ interactions with each other and their teacher. The analyses show a progression towards more scientific student drawings over the course of a lesson. This progression was made possible by sustained attention to critical details in the drawings, and the drawings and interactions were instrumental in developing a more sophisticated understanding of the mechanisms behind the greenhouse effect. IA provides important analytical insights into students’ interest in the situation, which is at the heart of social semiotics. Social semiotics offers insight into the nuances of students’ interpretations of the world and how they relate to the practices of disciplinary science.
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| 29. |
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| 30. |
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| 31. |
- Knain, Erik, et al.
(author)
-
Representing to learn in science education : Theoretical framework and analytical approaches
- 2017
-
In: Acta Didactica Norge - tidsskrift for fagdidaktisk forsknings- og utviklingsarbeid i Norge. - : University of Oslo Library. - 1504-9922. ; :3
-
Journal article (peer-reviewed)abstract
- Being able to engage with science representations, such as graphs, drawings, animations, gestures and written and verbal texts lies at the heart of scientific literacy. This article introduces the design-based research project Representations and Participation in School Science (REDE), which aims to investigate new aspects of how representations create learning and teaching opportunities in school science in lower and secondary school. It does so by scrutinising the role of representations in three areas of science education: the learning of science content, socio-scientific issues (SSI) and the nature of science. Central to the REDE project is the development of teaching designs whereby students’ and teachers’ engagement with various forms of representations are at the core of learning activities. The teaching designs are developed by teachers together with the researchers in REDE and are tested by the teachers and their students at three partner schools. In this article, we outline the theoretical framework of the project, which is based on scientific literacy and the notion of a ‘third space’. We also introduce the design principles that inform the development of the teaching designs, as well as the two main analytical approaches that we use to analyse students’ and teachers’ engagement with science representations: multimodal analysis and interaction analysis. Finally, we illustrate the potential of the theoretical framework, the design principles and the multimodal analysis in contributing to the investigations in REDE. We do so by presenting and discussing analyses of three empirical cases from classrooms where students worked with teaching designs that focus on representations.
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| 32. |
- Knain, Erik, et al.
(author)
-
The role of representations in students' argumentation on SSI
- 2017
-
Conference paper (other academic/artistic)abstract
- This paper reports on a study that investigates how visual representations support students’ learning in the context of socio-scientific issues (SSI). SSI often require students to apply science knowledge in order to deal with conflicts of interest. An aspect of SSI teaching and learning that is commonly held to be important is argumentation, where claims are supported with evidence. However, almost no studies have been carried out that focus on the use of evidence afforded by visual representations. In Norway, there is currently a conflict between the government and non-governmental organisations regarding whether Norwegian off-shore oil exploration should be extended or not. Two recent chronicles – one from each part in the conflict, made the starting point for the educational setting from which our data was collected. Groups of students wrote texts arguing either for or against further exploration. A range of visual representations related to the topic had been collected by the teacher and the researchers. The students made a selection from this collection and incorporated the selected representations into their texts. Video data was collected using head-mounted cameras. Analysis suggests that student learning is enhanced when they get opportunities to create, critique and revise their representations and texts. Such opportunities were therefore included in the design for learning. Our analyses reveal processes involved when the students selected and orchestrated multimodal representations into their argumentative texts. However, an implication from our study is that students appear to be more familiar with the create phase, than with the critique and revise phases. These results suggest that students need more instructional support in, and practice of, these phases.
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| 33. |
- Kucharzewska, Paulina, et al.
(author)
-
Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development.
- 2013
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:18, s. 7312-7317
-
Journal article (peer-reviewed)abstract
- Hypoxia, or low oxygen tension, is a major regulator of tumor development and aggressiveness. However, how cancer cells adapt to hypoxia and communicate with their surrounding microenvironment during tumor development remain important questions. Here, we show that secreted vesicles with exosome characteristics mediate hypoxia-dependent intercellular signaling of the highly malignant brain tumor glioblastoma multiforme (GBM). In vitro hypoxia experiments with glioma cells and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins (e.g., matrix metalloproteinases, IL-8, PDGFs, caveolin 1, and lysyl oxidase), several of which were associated with poor glioma patient prognosis. We show that exosomes derived from GBM cells grown at hypoxic compared with normoxic conditions are potent inducers of angiogenesis ex vivo and in vitro through phenotypic modulation of endothelial cells. Interestingly, endothelial cells were programmed by GBM cell-derived hypoxic exosomes to secrete several potent growth factors and cytokines and to stimulate pericyte PI3K/AKT signaling activation and migration. Moreover, exosomes derived from hypoxic compared with normoxic conditions showed increased autocrine, promigratory activation of GBM cells. These findings were correlated with significantly enhanced induction by hypoxic compared with normoxic exosomes of tumor vascularization, pericyte vessel coverage, GBM cell proliferation, as well as decreased tumor hypoxia in a mouse xenograft model. We conclude that the proteome and mRNA profiles of exosome vesicles closely reflect the oxygenation status of donor glioma cells and patient tumors, and that the exosomal pathway constitutes a potentially targetable driver of hypoxia-dependent intercellular signaling during tumor development.
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| 34. |
- Larsson, Anna-Maria, et al.
(author)
-
Erythropoietin Receptor Expression and Correlation to Tamoxifen Response and Prognosis in Breast Cancer.
- 2009
-
In: Clinical Cancer Research. - 1078-0432. ; 15:17, s. 5552-5559
-
Journal article (peer-reviewed)abstract
- PURPOSE: The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen. EXPERIMENTAL DESIGN: EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS). RESULTS: EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression. CONCLUSION: EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior. (Clin Cancer Res 2009;15(17):5552-9).
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| 35. |
- Larsson, Erik, 1975, et al.
(author)
-
Discovery of microvascular miRNAs using public gene expression data : miR-145 is expressed in pericytes and is a regulator of Fli1
- 2009
-
In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 1:11, s. 108-
-
Journal article (peer-reviewed)abstract
- BACKGROUNDA function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets.METHODSBioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber.RESULTSmiR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro.CONCLUSIONSmiR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature.
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| 36. |
- Lovén, Jakob, et al.
(author)
-
MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma.
- 2010
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:4, s. 1553-8
-
Journal article (peer-reviewed)abstract
- MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 approximately 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.
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| 37. |
- Löfstedt, Tobias, et al.
(author)
-
HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells.
- 2009
-
In: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 315:11, s. 1924-1936
-
Journal article (peer-reviewed)abstract
- Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.
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| 38. |
- Löfstedt, Tobias, et al.
(author)
-
Hypoxia inducible factor-2alpha in cancer.
- 2007
-
In: Cell Cycle. - 1551-4005. ; 6:8, s. 919-926
-
Journal article (peer-reviewed)abstract
- Poorly oxygenated ( hypoxic) tumors are frequently more aggressive compared to corresponding tumors that are better oxygenated. Adaptation to hypoxia is primarily mediated by two closely related hypoxia inducible transcription factor complexes, HIF-1 and HIF-2, which become stabilized and activated at low oxygen levels. Whether HIF-1 and HIF-2 have different roles in tumorigenesis is an open question and an issue we discuss. With focus on HIF-2, we summarize reported phenotypical changes of HIF genetic models and HIF expression patterns during normal development, in adult non - malignant tissues and in tumors. We further address the much - discussed subject of target gene preferences between HIF-1 and HIF-2, given that both transcription factors bind to the same DNA motif. Finally, we also discuss the observations that the oxygen - sensitive HIF-2 alpha subunit is accumulated and active under non - hypoxic conditions as exemplified by HIF-2 alpha expressing tumor macrophages and neuroblastoma cells located in seemingly well - vascularized tumor regions and how this phenomenon is related to tumor aggressiveness.
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| 39. |
- Mark, Andreas, 1980, et al.
(author)
-
Modeling and Simulation of Paperboard Edge Wicking
- 2012
-
In: Nordic Pulp and Paper Research Journal. - 2000-0669 .- 0283-2631. ; 27:2, s. 397-402
-
Journal article (peer-reviewed)abstract
- When liquid packaging board is made aseptic in the filling machine the unsealed edges of the board are exposed to hydrogen peroxide. A high level of liquid penetration may lead to aesthetic as well as functional defects. To be able to make a priori predictions of the edge wicking properties of a certain paperboard material is therefore of great interest to paper industry as well as to packaging manufacturers. The aim of this paper is to present a new analytical theory for prediction of the edge wicking properties of paperboard. The theory is based on Darcy’s law and the ideal gas law to describe the physical behavior of water flow in paperboard. The theory is compared to a recently published multi-scale framework and with pressurized edge wick experiments. The agreement is very good for paperboard samples of different sizes. The conclusion from the work is that both analytical theory and detailed simulations are useful to predict edge wicking properties of paperboard material.
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| 40. |
- Mark, Andreas, 1980, et al.
(author)
-
Multi-scale simulation of paperboard edge wicking using a fiber-resolving virtual paper model
- 2012
-
In: Tappi Journal. - 0734-1415. ; 11:6, s. 9-16
-
Journal article (peer-reviewed)abstract
- When liquid packaging board is made aseptic in the filling machine the unsealed edges of the board are exposed to hydrogen peroxide. A high level of liquid penetration may lead to aesthetic as well as functional defects. To be able to make a priori predictions of the edge wicking properties of a certain paperboard material is therefore of great interest to paper industry as well as to packaging manufacturers. In this paper a multi-scale framework is proposed that allows for detailed simulation of the edge wicking process.On the fiber micro-scale virtual paper models are generated based on input from tomographic and SEM images. A pore morphology method is used to calculate capillary pressure curves, and on the active pores one-phase flow simulations are performed for relative permeabilities. The results as functions of saturation and porosity are stored in a database. The database is used as input for two-phase flow simulations on the paper macro-scale. The resulting fluid penetration is validated against pressurized edge wick measurements on paper lab sheets with very good agreement. The proposed multi-scale approach can be used to increase the understanding of how edge wicking in paperboard packages depends on the micro-structure.
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| 41. |
- Mark, Andreas, 1980, et al.
(author)
-
Multi-scale simulation of paperboard edge wicking using a fiber-resolving virtual paper model
- 2011
-
In: Progress in Paper Physics Seminar. - 9783851251630 ; , s. 41-47
-
Conference paper (peer-reviewed)abstract
- When liquid paperboard based package material ismade aseptic, unsealed edges of the board are exposedto a liquid front which in some circumstances may soakthe material to some extent. This is not desired since itmay lead to aesthetic as well as functional defects. Inorder to make a priori predictions of the edge wickingproperties of a given paper material, something whichis of great interest to paperboard industry as well aspackaging manufacturers, micro simulations are required.To calculate the penetration of fluid in the open edgeof a paper sheet a multi-scale framework is developed.On the fiber micro-scale, virtual paper models are generatedin PaperGeo [6]. In IBOFlow [7] a pore morphologymethod is used to calculate capillary pressurecurves, and the active pores one-phase flow simulationsare performed for relative permeabilities. Theresult is a database of capillary pressure curves andrelative permeabilities as functions of saturation andporosity. The database is used as an input for a twophaseflow simulation on a 2D virtual macro sheet tocalculate the penetration of fluid in the paper. Themulti-scale framework is validated against pressurizededge wick measurements with good agreement.
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| 42. |
- Mestdagh, P., et al.
(author)
-
An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours
- 2010
-
In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 29:24, s. 3583-3592
-
Journal article (peer-reviewed)abstract
- Different classes of non-coding RNAs, including microRNAs, have recently been implicated in the process of tumourigenesis. In this study, we examined the expression and putative functions of a novel class of non-coding RNAs known as transcribed ultraconserved regions (T-UCRs) in neuroblastoma. Genome-wide expression pro. ling revealed correlations between specific T-UCR expression levels and important clinicogenetic parameters such as MYCN amplification status. A functional genomics approach based on the integration of multi-level transcriptome data was adapted to gain insights into T-UCR functions. Assignments of T-UCRs to cellular processes such as TP53 response, differentiation and proliferation were verified using various cellular model systems. For the first time, our results de. ne a T-UCR expression landscape in neuroblastoma and suggest widespread T-UCR involvement in diverse cellular processes that are deregulated in the process of tumourigenesis. Oncogene (2010) 29, 3583-3592; doi:10.1038/onc.2010.106; published online 12 April 2010
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| 43. |
- Mestdagh, Pieter, et al.
(author)
-
The miR-17-92 MicroRNA Cluster Regulates Multiple Components of the TGF-beta Pathway in Neuroblastoma
- 2010
-
In: Molecular Cell. - : Elsevier BV. - 1097-4164 .- 1097-2765. ; 40:5, s. 762-773
-
Journal article (peer-reviewed)abstract
- The miR-17-92 microRNA cluster is often activated in cancer cells, but the identity of its targets remains elusive. Using SILAC and quantitative mass spectrometry, we examined the effects of activation of the miR-17-92 cluster on global protein expression in neuroblastoma (NB) cells. Our results reveal cooperation between individual miR-17-92 miRNAs and implicate miR-17-92 in multiple hallmarks of cancer, including proliferation and cell adhesion. Most importantly, we show that miR-17-92 is a potent inhibitor of TGF-beta signaling. By functioning both upstream and downstream of pSMAD2, miR-17-92 activation triggers downregulation of multiple key effectors along the TGF-beta signaling cascade as well as direct inhibition of TGF-beta-responsive genes.
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| 44. |
- Noguera, Rosa, et al.
(author)
-
HIF-1{alpha} and HIF-2{alpha} Are Differentially Regulated In vivo in Neuroblastoma: High HIF-1{alpha} Correlates Negatively to Advanced Clinical Stage and Tumor Vascularization.
- 2009
-
In: Clinical Cancer Research. - 1078-0432. ; 15:23, s. 7130-7136
-
Journal article (peer-reviewed)abstract
- PURPOSE: Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma. EXPERIMENTAL DESIGN: Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1alpha, HIF-2alpha, VEGF, and CD31 proteins. Both fraction of positive cells and staining intensity were evaluated and protein levels were correlated with each other and with clinical variables. RESULTS: Although high levels of both HIF-1alpha (P < 0.001) and HIF-2alpha (P < 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1alpha (P = 0.002) and VEGF (P < 0.001), but not HIF-2alpha, correlated negatively to vascularization as determined by CD31 staining abundance. VEGF expression or degree of vascularization did not correlate with tumor stage or overall survival. High HIF-1alpha levels correlated with low tumor stage (P < 0.001) and were associated with a favorable patient prognosis (P = 0.08). CONCLUSIONS: The discordant results on expression of HIF-1alpha and HIF-2alpha suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1alpha and favorable outcome stresses the importance of discriminating HIF-2alpha from HIF-1alpha expression and has implications for using HIFs as treatment targets. (Clin Cancer Res 2009;15(23):OF1-7).
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| 45. |
- Orre, Lukas Minus, et al.
(author)
-
SubCellBarCode : Proteome-wide Mapping of Protein Localization and Relocalization
- 2019
-
In: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 73:1, s. 166-182.e7
-
Journal article (peer-reviewed)abstract
- Subcellular localization is a main determinant of protein function; however, a global view of cellular proteome organization remains relatively unexplored. We have developed a robust mass spectrometry-based analysis pipeline to generate a proteome-wide view of subcellular localization for proteins mapping to 12,418 individual genes across five cell lines. Based on more than 83,000 unique classifications and correlation profiling, we investigate the effect of alternative splicing and protein domains on localization, complex member co-localization, cell-type-specific localization, as well as protein relocalization after growth factor inhibition. Our analysis provides information about the cellular architecture and complexity of the spatial organization of the proteome; we show that the majority of proteins have a single main subcellular location, that alternative splicing rarely affects subcellular location, and that cell types are best distinguished by expression of proteins exposed to the surrounding environment. The resource is freely accessible via www.subcellbarcode.org.
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| 46. |
- Pietras, Alexander, et al.
(author)
-
HIF-2 alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
- 2009
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:39, s. 16805-16810
-
Journal article (peer-reviewed)abstract
- High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy.
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| 47. |
- Påhlman, Sven, et al.
(author)
-
Notch signaling in neuroblastoma.
- 2004
-
In: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 14:5, s. 365-373
-
Journal article (peer-reviewed)
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| 48. |
- Ringnér, Markus, et al.
(author)
-
GOBO: Gene Expression-Based Outcome for Breast Cancer Online.
- 2011
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:3
-
Journal article (peer-reviewed)abstract
- Microarray-based gene expression analysis holds promise of improving prognostication and treatment decisions for breast cancer patients. However, the heterogeneity of breast cancer emphasizes the need for validation of prognostic gene signatures in larger sample sets stratified into relevant subgroups. Here, we describe a multifunctional user-friendly online tool, GOBO (http://co.bmc.lu.se/gobo), allowing a range of different analyses to be performed in an 1881-sample breast tumor data set, and a 51-sample breast cancer cell line set, both generated on Affymetrix U133A microarrays. GOBO supports a wide range of applications including: 1) rapid assessment of gene expression levels in subgroups of breast tumors and cell lines, 2) identification of co-expressed genes for creation of potential metagenes, 3) association with outcome for gene expression levels of single genes, sets of genes, or gene signatures in multiple subgroups of the 1881-sample breast cancer data set. The design and implementation of GOBO facilitate easy incorporation of additional query functions and applications, as well as additional data sets irrespective of tumor type and array platform.
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| 49. |
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| 50. |
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