| 1. |
- Nasr, Patrik, et al.
(författare)
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A rapid, non-invasive, clinical surveillance for CachExia, sarcopenia, portal hypertension, and hepatocellular carcinoma in end-stage liver disease : the ACCESS-ESLD study protocol
- 2023
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Ingår i: BMC Gastroenterology. - : BioMed Central (BMC). - 1471-230X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Liver cirrhosis, the advanced stage of many chronic liver diseases, is associated with escalated risks of liver-related complications like decompensation and hepatocellular carcinoma (HCC). Morbidity and mortality in cirrhosis patients are linked to portal hypertension, sarcopenia, and hepatocellular carcinoma. Although conventional cirrhosis management centered on treating complications, contemporary approaches prioritize preemptive measures. This study aims to formulate novel blood- and imaging-centric methodologies for monitoring liver cirrhosis patients.METHODS: In this prospective study, 150 liver cirrhosis patients will be enrolled from three Swedish liver clinics. Their conditions will be assessed through extensive blood-based markers and magnetic resonance imaging (MRI). The MRI protocol encompasses body composition profile with Muscle Assement Score, portal flow assessment, magnet resonance elastography, and a abbreviated MRI for HCC screening. Evaluation of lifestyle, muscular strength, physical performance, body composition, and quality of life will be conducted. Additionally, DNA, serum, and plasma biobanking will facilitate future investigations.DISCUSSION: The anticipated outcomes involve the identification and validation of non-invasive blood- and imaging-oriented biomarkers, enhancing the care paradigm for liver cirrhosis patients. Notably, the temporal evolution of these biomarkers will be crucial for understanding dynamic changes.TRIAL REGISTRATION: Clinicaltrials.gov, registration identifier NCT05502198. Registered on 16 August 2022. Link: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05502198 .
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| 2. |
- Andreasson, Martin, 1993-, et al.
(författare)
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Dynamics of related and unrelated digital diversification in established firms : Strategies, programs, process, and outcomes
- 2024
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Ingår i: Technological forecasting & social change. - : Elsevier. - 0040-1625 .- 1873-5509. ; 202
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Tidskriftsartikel (refereegranskat)abstract
- Research on digital transformation focuses on business models and technological innovation but it often lacks a detailed exploration of how firms develop, execute, and evaluate related and unrelated digital diversification strategies. To address this gap, this study employs a multiple case study approach to uncover the varied processes and outcomes of implementing digital diversification programs in established firms. The findings reveal that established firms frequently refine and adjust their digital diversification strategies to achieve desired results. Specifically, related digital diversification strategies benefit from well-defined market segments, clear technological focus, and robust senior management support. In contrast, unrelated digital diversification strategies thrive through extensive exploration and experimentation with novel digital technologies and markets, reduced senior managerial intervention and increased middle- and lower-level management involvement. Semi-related digital diversification strategies, which incorporate elements of both related and unrelated approaches, often encounter tensions owing to conflicting traditional and new program execution methods, posing significant realization challenges. Key factors identified as instrumental in the success of digital diversification strategies include technology, markets, management & organization, and program execution. The study concludes by discussing the managerial and academic implications and offers recommendations for future research in this domain.
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| 3. |
- Ayoun Alsoud, Rami, et al.
(författare)
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Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development
- 2023
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.
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| 4. |
- Azar, Jimmy, et al.
(författare)
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Automated Classification of Glandular Tissue by Statistical Proximity Sampling
- 2015
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Ingår i: International Journal of Biomedical Imaging. - : Hindawi Limited. - 1687-4188 .- 1687-4196.
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Tidskriftsartikel (refereegranskat)abstract
- Due to the complexity of biological tissue and variations in staining procedures, features that are based on the explicit extraction of properties from subglandular structures in tissue images may have difficulty generalizing well over an unrestricted set of images and staining variations. We circumvent this problem by an implicit representation that is both robust and highly descriptive, especially when combined with a multiple instance learning approach to image classification. The new feature method is able to describe tissue architecture based on glandular structure. It is based on statistically representing the relative distribution of tissue components around lumen regions, while preserving spatial and quantitative information, as a basis for diagnosing and analyzing different areas within an image. We demonstrate the efficacy of the method in extracting discriminative features for obtaining high classification rates for tubular formation in both healthy and cancerous tissue, which is an important component in Gleason and tubule-based Elston grading. The proposed method may be used for glandular classification, also in other tissue types, in addition to general applicability as a region-based feature descriptor in image analysis where the image represents a bag with a certain label (or grade) and the region-based feature vectors represent instances.
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| 5. |
- Azar, Jimmy, 1984-
(författare)
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Automated Tissue Image Analysis Using Pattern Recognition
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Automated tissue image analysis aims to develop algorithms for a variety of histological applications. This has important implications in the diagnostic grading of cancer such as in breast and prostate tissue, as well as in the quantification of prognostic and predictive biomarkers that may help assess the risk of recurrence and the responsiveness of tumors to endocrine therapy.In this thesis, we use pattern recognition and image analysis techniques to solve several problems relating to histopathology and immunohistochemistry applications. In particular, we present a new method for the detection and localization of tissue microarray cores in an automated manner and compare it against conventional approaches.We also present an unsupervised method for color decomposition based on modeling the image formation process while taking into account acquisition noise. The method is unsupervised and is able to overcome the limitation of specifying absorption spectra for the stains that require separation. This is done by estimating reference colors through fitting a Gaussian mixture model trained using expectation-maximization.Another important factor in histopathology is the choice of stain, though it often goes unnoticed. Stain color combinations determine the extent of overlap between chromaticity clusters in color space, and this intrinsic overlap sets a main limitation on the performance of classification methods, regardless of their nature or complexity. In this thesis, we present a framework for optimizing the selection of histological stains in a manner that is aligned with the final objective of automation, rather than visual analysis.Immunohistochemistry can facilitate the quantification of biomarkers such as estrogen, progesterone, and the human epidermal growth factor 2 receptors, in addition to Ki-67 proteins that are associated with cell growth and proliferation. As an application, we propose a method for the identification of paired antibodies based on correlating probability maps of immunostaining patterns across adjacent tissue sections.Finally, we present a new feature descriptor for characterizing glandular structure and tissue architecture, which form an important component of Gleason and tubule-based Elston grading. The method is based on defining shape-preserving, neighborhood annuli around lumen regions and gathering quantitative and spatial data concerning the various tissue-types.
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| 6. |
- Azar, Jimmy C., et al.
(författare)
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Image segmentation and identification of paired antibodies in breast tissue
- 2014
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Ingår i: Computational & Mathematical Methods in Medicine. - : Hindawi Limited. - 1748-670X .- 1748-6718. ; , s. 647273:1-11
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Tidskriftsartikel (refereegranskat)abstract
- Comparing staining patterns of paired antibodies designed towards a specific protein but toward different epitopes of the protein provides quality control over the binding and the antibodies' ability to identify the target protein correctly and exclusively. We present a method for automated quantification of immunostaining patterns for antibodies in breast tissue using the Human Protein Atlas database. In such tissue, dark brown dye 3,3'-diaminobenzidine is used as an antibody-specific stain whereas the blue dye hematoxylin is used as a counterstain. The proposed method is based on clustering and relative scaling of features following principal component analysis. Our method is able (1) to accurately segment and identify staining patterns and quantify the amount of staining and (2) to detect paired antibodies by correlating the segmentation results among different cases. Moreover, the method is simple, operating in a low-dimensional feature space, and computationally efficient which makes it suitable for high-throughput processing of tissue microarrays.
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| 7. |
- Baccarani, Michele, et al.
(författare)
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European LeukemiaNet recommendations for the management of chronic myeloid leukemia : 2013
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 122:6, s. 872-884
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Forskningsöversikt (refereegranskat)abstract
- Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels <= 10% at 3 months, <1% at 6 months, and <= 0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph1]>95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved. (Blood. 2013; 122(6):872-884)
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| 8. |
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| 9. |
- Björnfot, Anders, et al.
(författare)
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Lessons learned from successful value stream mapping (VSM)
- 2011
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Ingår i: Proceedings of IGLC-19. - Lima : Fondo Ed. Pontificia Universidad Católica del Peru. - 9781622768233 ; , s. 163-173
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- To improve, it’s crucial to see! Vital characteristics of Lean are visualisation and transparency, i.e. allowing everyone to see all what occurs in production. A common tool for this purpose is Value Stream Mapping (VSM). Due to varying flows, performing a successful VSM in construction confers additional challenges. In this paper, lessons learned from successful VSM studies in construction are provided.Three VSM case studies were performed at different companies ranging from patio door manufacturing to kitchen cabinet assembly. Lessons learned can be structured into three phases; preparing the VSM (selecting “value stream leaders” and VSM team, clarifying values, etc.), performing the VSM (use of mapping tools, approximation of key indicators, waste identification, etc.), and following-up the VSM (Plan-Do-Check-Act, evaluating customer values, etc.).For the involved companies, the lessons learned imply the start of a “Lean journey” even though the involved companies found it difficult to relate VSM improvements to business strategies. Consequently, there are opportunities to further improve the application of VSM. However, it’s important to remember that VSM is about the straight-forward visualisation of flows and that these flows are made transparent for the whole organisation.
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| 10. |
- Bojrup, Martin, et al.
(författare)
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A Dual Purpose battery Charger for Electric Vehicles
- 1998
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Ingår i: PESC 98 Conference Proceedings. ; , s. 565-570
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Konferensbidrag (refereegranskat)abstract
- Abstract in UndeterminedA dual purpose, high power, off board battery charger for electric vehicles is presented. For higher viability and increased usage of the charger, grid conditioning capabilities are included in the concept. Conventional power electronic converter topologies are used in a new application, which combines fast EV battery charging with active filtering. Furthermore bi-directional power flow capabilities are provided to accommodate grid peak power requirements. Both simulation and experimental results are presented in this paper which demonstrate the capabilities of the new charger.
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| 11. |
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| 12. |
- Emborg, Mats, et al.
(författare)
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Designing robust SCC for industrial construction with cast in place concrete
- 2005
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Ingår i: Second North American Conference on the Design and Use of Self-Consolidating Concrete [and] Fourth International RILEM Symposium on Self-Compacting Concrete; [October 30 - November 2, 2005];Second North American Conference on the Design and Use of Self-Consolidating Concrete [and] Fourth International RILEM Symposium on Self-Compacting Concrete; [October 30 - November 2, 2005. - Hanley Wood. ; , s. 1251-1257
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Konferensbidrag (refereegranskat)
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| 13. |
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| 14. |
- Gallo, Yann, et al.
(författare)
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Investigation of Late-Cycle Soot Oxidation Using Laser Extinction and In-Cylinder Gas Sampling at Varying Inlet Oxygen Concentrations in Diesel Engines
- 2017
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Ingår i: Fuel. - : Elsevier BV. - 1873-7153 .- 0016-2361. ; 193, s. 308-314
-
Tidskriftsartikel (refereegranskat)abstract
- This study focuses on the relative importance of O2 and OH as oxidizers of soot during the late cycle in diesel engines, where the soot oxidation is characterized in an optically accessible engine using laser extinction measurements. These are combined with in cylinder gas sampling data from a single cylinder engine fitted with a fast gas sampling valve. Both measurements confirm that the in-cylinder soot oxidation slows down when the inlet concentration of O2 is reduced. A 38% decrease in intake O2 concentration reduces the soot oxidation rate by 83%, a non-linearity suggesting that O2 in itself is not the main soot oxidizing species. Chemical kinetics simulations of OH concentrations in the oxidation zone and estimates of the OH soot oxidation rates point towards OH being the dominant oxidizer.
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| 15. |
- Glimelius, Ingrid, 1975-, et al.
(författare)
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Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin's Lymphoma : a population-based study
- 2011
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 87:3, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Classical Hodgkin’s lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype.Methods: In a population-based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n = 448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein-x (EPX) gene polymorphisms were determined. Associations were assessed in regression models.Results: Self-reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR) = 2.22, 95% CI 1.06–4.64, P = 0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs) = 1.84, 95% CI 1.02–3.30, P = 0.04]. Lower number of eosinophils was seen in Epstein–Barr virus (EBV)-positive tumours (univariate RL = 0.52, 95% CI 0.3–0.9, P = 0.02) and in older patients (univariate RL = 0.85, 95% CI 0.73–0.99, P = 0.03). Well-known factors such as young age, female sex and EBV-negative status predicted nodular sclerosis histology.Conclusion: The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.
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| 16. |
- Glimelius, Ingrid, et al.
(författare)
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Tissue microarray and digital image analysis : a methodological study with special reference to the microenvironment in Hodgkin lymphoma
- 2012
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Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 61:1, s. 26-32
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Cancer research has moved from solely investigating the tumour cells to also including analysis of the tumour microenvironment; however, the methods utilized have not been evaluated for this change. The aim of this study was to compare tissue microarrays (TMA) to whole tissue sections (WS) with regard to cells in the tumour microenvironment. Manual evaluation and digital image analyses (DIA) were utilized and also compared.Methods and results: TMA slides from 117 Hodgkin lymphoma patients were immunostained for forkhead box protein 3 (FoxP3) [identifying regulatory T cells (T(reg) )], and 39 corresponding WS were also analysed. Manual evaluation and DIA were utilized for all patients on both the TMA and the WS. A correlation coefficient of 0.83 was obtained for the proportion of T(reg) in TMA versus WS using manual evaluation and a correlation coefficient of 0.77 with DIA. T(reg) counts using manual evaluation correlated in turn with DIA, with a coefficient of 0.79 for the 117 TMA sections and 0.65 for the 39 WS.Conclusion: Because a high correlation was observed between TMA and WS, TMA can be utilized when evaluating cells in the tumour microenvironment. DIA appears to provide a reliable measurement method, provided that manual control of the tumour slides is conducted.
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| 17. |
- Grossmann, Igor, et al.
(författare)
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Insights into the accuracy of social scientists' forecasts of societal change
- 2023
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Ingår i: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7, s. 484-501
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Tidskriftsartikel (refereegranskat)abstract
- How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing the accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. After we provided them with historical trend data on the relevant domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N = 86 teams and 359 forecasts), with an opportunity to update forecasts on the basis of new data six months later (Tournament 2; N = 120 teams and 546 forecasts). Benchmarking forecasting accuracy revealed that social scientists' forecasts were on average no more accurate than those of simple statistical models (historical means, random walks or linear regressions) or the aggregate forecasts of a sample from the general public (N = 802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models and based predictions on prior data. How accurate are social scientists in predicting societal change, and what processes underlie their predictions? Grossmann et al. report the findings of two forecasting tournaments. Social scientists' forecasts were on average no more accurate than those of simple statistical models.
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| 18. |
- Gunnarsson, Fredrik, et al.
(författare)
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Downtilted Base Station Antennas - A Simulation Model Proposal and Impact on HSPA and LTE Performance
- 2008
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Ingår i: Proceedings of the 68th IEEE Vehicular Technology Conference. - 9781424417223 - 9781424417216 ; , s. 1-5
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Konferensbidrag (refereegranskat)abstract
- This paper proposes a low-complexity model for vertical antenna radiation patterns, e.g. for inclusion in system- level simulations. They can be seen as extensions to the horizontal radiation pattern model used in 3GPP simulation scenarios. The model is verified against and compared to predicted and measured data from real networks. The impact on system-level performance is also investigated. It is seen that using the proposed model, simulated geometry distributions and soft handover statistics closely matching those of real networks may be achieved. The analysis also concludes that many real networks have better cell isolation than what is modeled by the 3GPP antenna model. As a consequence, the horizontal radiation pattern model significantly under-estimates the system level performance in such networks. Furthermore, the proposed model is used to assess the LTE and HSPA system-level performance for realistic scenarios.
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| 19. |
- Hagberg, Anette, et al.
(författare)
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Gene expression analysis identifies a genetic signature potentially associated with response to alpha-IFN in chronic phase CML patients
- 2007
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 31:7, s. 931-938
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Tidskriftsartikel (refereegranskat)abstract
- Microarray-based gene expression analysis was performed on diagnostic chronic phase CML patient samples prior to interferon treatment. Fifteen patient samples corresponding to six cytogenetic responders and nine non-responders were included. Genes differentially expressed between responder and non-responder patients were listed and a subsequent leave-one-out cross validation (LOOV) procedure showed that the top 20 genes allowed the highest prediction accuracy. The relevant genes were quantified by real-time PCR that supported the microarray results. We conclude that it might be possible to use gene expression analysis to predict future response to interferon in CML diagnostic samples.
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| 20. |
- Hedström, Gustav, et al.
(författare)
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Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)
- 2013
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Ingår i: International Journal of Hematology. - : Springer Science and Business Media LLC. - 0925-5710 .- 1865-3774. ; 97:4, s. 465-471
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL.
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| 21. |
- Hjorth-Hansen, Henrik, et al.
(författare)
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Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006)
- 2015
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 94:3, s. 243-250
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Tidskriftsartikel (refereegranskat)abstract
- We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100mg QD or imatinib 400mg QD and report outcome as an intention-to-treat analysis with 36months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3months in 36% vs. 8% (P=0.02), at 12months in 81% vs. 46% (P=0.02) and at 18months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6months onwards, reaching 61% vs. 21% (P<0.05) at 36months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.
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| 22. |
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| 23. |
- Hoffmann, V S, et al.
(författare)
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Treatment and outcome of 2904 CML patients from the EUTOS population-based registry
- 2017
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:3, s. 593-601
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Tidskriftsartikel (refereegranskat)abstract
- The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.Leukemia advance online publication, 23 September 2016; doi:10.1038/leu.2016.246.
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| 24. |
- Håkansson, Joakim, et al.
(författare)
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De- and recellularized urethral reconstruction with autologous buccal mucosal cells implanted in an ovine animal model
- 2023
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Ingår i: Biomedizinische Technik (Berlin. Zeitschrift). - : De Gruyter Open Ltd. - 1862-278X .- 0013-5585. ; 68:5, s. 493-
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Tidskriftsartikel (refereegranskat)abstract
- Patients with urethral stricture due to any type of trauma, hypospadias or gender dysphoria suffer immensely from impaired capacity to urinate and are in need of a new functional urethra. Tissue engineering with decellularization of a donated organ recellularized with cells from the recipient patient has emerged as a promising alternative of advanced therapy medicinal products. The aim of this pilot study was to develop an ovine model of urethral transplantation and to produce an individualized urethra graft to show proof of function in vivo. Donated urethras from ram abattoir waste were decellularized and further recellularized with autologous buccal mucosa epithelial cells excised from the recipient ram and expanded in vitro. The individualized urethral grafts were implanted by reconstructive surgery in rams replacing 2.5 ± 0.5 cm of the native penile urethra. After surgery optimization, three ram had the tissue engineered urethra implanted for one month and two out of three showed a partially regenerated epithelium. Further adjustments of the model are needed to achieve a satisfactory proof-of-concept; however, we interpret these findings as a proof of principle and a possible path to develop a functional tissue engineered urethral graft with de- and recellularization and regeneration in vivo after transplantation.
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| 25. |
- Höglund, Martin, et al.
(författare)
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Epidemiology of chronic myeloid leukaemia : an update
- 2015
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Ingår i: Annals of Hematology. - : Springer Science and Business Media LLC. - 0939-5555 .- 1432-0584. ; 94, s. S241-S247
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Forskningsöversikt (refereegranskat)abstract
- National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7-1.0/100,000, a median age at diagnosis of 57-60 years and a male/female ratio of 1.2-1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10-12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research.
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| 26. |
- Höglund, Martin, et al.
(författare)
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Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry
- 2013
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 122:7, s. 1284-1292
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Tidskriftsartikel (refereegranskat)abstract
- Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100 000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (andlt;70 years) and 79% for older (andgt;80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.
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| 27. |
- Issac Niwas, Swamidoss, et al.
(författare)
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Automated classification of immunostaining patterns in breast tissue from the Human Protein Atlas
- 2012
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Ingår i: Histopathology Image Analysis (HIMA).
-
Konferensbidrag (refereegranskat)abstract
- Background:The Human Protein Atlas (HPA) is an effort to map the location of all human proteins (http://www.proteinatlas.org/ ). It contains a large number of histological images of sections from human tissue. Tissue micro arrays are imaged by a slide scanning microscope, and each image represents a thin slice of a tissue core with a dark brown antibody specific stain and a blue counter stain. When generating antibodies for protein profiling of the human proteome, an important step in the quality control is to compare staining patterns of different antibodies directed towards the same protein. This comparison is an ultimate control that the antibody recognizes the right protein. In this paper, we propose and evaluate different approaches for classifying sub-cellular antibody staining patterns in breast tissue samples.Methods and Material:The proposed methods include the computation of various features including gray level co-occurrence matrix (GLCM) features, complex wavelet co-occurrence matrix (CWCM) features and WND-CHARM-inspired features. The extracted features are used into two different multivariate classifiers (SVM and LDA classifier). Before extracting features, we use color deconvolution to separate different tissue components, such as the brownly stained positive regions and the blue cellular regions, in the immuno-stained TMA images of breast tissue.Results:Good results have been obtained by using the combinations of GLCM and wavelets and texture features, edge features, histograms, transforms, etc. (WND-CHARM). The proposed complex wavelet features and the WND-CHARM features have accuracy similar to that of a human expert.Conclusions:Both human experts and the proposed automated methods have difficulties discriminating between nuclear and cytoplasmic staining patterns. This is to a large extent due to mixed staining of nucleus and cytoplasm. Methods for quantification of staining patterns in histopathology have many applications, ranging from antibody quality control to tumour grading.
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| 28. |
- Issac Niwas, Swamidoss, et al.
(författare)
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Automated classification of immunostaining patterns in breast tissue from the Human Protein Atlas
- 2013
-
Ingår i: Journal of Pathology Informatics. - : Elsevier BV. - 2229-5089 .- 2153-3539. ; 4:14
-
Tidskriftsartikel (refereegranskat)abstract
- Background:The Human Protein Atlas (HPA) is an effort to map the location of all human proteins (http://www.proteinatlas.org/). It contains a large number of histological images of sections from human tissue. Tissue micro arrays (TMA) are imaged by a slide scanning microscope, and each image represents a thin slice of a tissue core with a dark brown antibody specific stain and a blue counter stain. When generating antibodies for protein profiling of the human proteome, an important step in the quality control is to compare staining patterns of different antibodies directed towards the same protein. This comparison is an ultimate control that the antibody recognizes the right protein. In this paper, we propose and evaluate different approaches for classifying sub-cellular antibody staining patterns in breast tissue samples.Materials and Methods:The proposed methods include the computation of various features including gray level co-occurrence matrix (GLCM) features, complex wavelet co-occurrence matrix (CWCM) features, and weighted neighbor distance using compound hierarchy of algorithms representing morphology (WND-CHARM)-inspired features. The extracted features are used into two different multivariate classifiers (support vector machine (SVM) and linear discriminant analysis (LDA) classifier). Before extracting features, we use color deconvolution to separate different tissue components, such as the brownly stained positive regions and the blue cellular regions, in the immuno-stained TMA images of breast tissue.Results:We present classification results based on combinations of feature measurements. The proposed complex wavelet features and the WND-CHARM features have accuracy similar to that of a human expert.Conclusions:Both human experts and the proposed automated methods have difficulties discriminating between nuclear and cytoplasmic staining patterns. This is to a large extent due to mixed staining of nucleus and cytoplasm. Methods for quantification of staining patterns in histopathology have many applications, ranging from antibody quality control to tumor grading.
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| 29. |
- Kumar, T K Sandeep, 1986-, et al.
(författare)
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Establishing a Novel Methodology to Correlate the Macroscopic and Microscopic Degree of Sintering inMagnetite Pellets during Induration
- 2018
-
Ingår i: Steel Research International. - : John Wiley & Sons. - 1611-3683 .- 1869-344X. ; 89:3
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Tidskriftsartikel (refereegranskat)abstract
- The quality of product pellets is a result of the physico-chemical phenomenainvolved in the induration process. Sintering is the primary phenomenon,and its degree or extent contributes substantially to the evolution of themetallurgical and mechanical properties of a pellet. During the induration ofmagnetite pellets, sintering proceeds through the oxidized and non-oxidizedmagnetite phases. Sintering of these phases has been previously studied ona single pellet at the macroscopic scale using an optical dilatometer. Adeeper understanding requires corroboration of these studies throughcharacterization at the microscopic scale. In the present work, the observationsrecorded at the microscopic scale are quantified using image processingtechniques to correlate them to the macroscopic measurements. Distancetransformation, which is an image processing principle, is adapted in a novelway to digitize the microstructures and to determine the degree of sinteringin a pellet quantitatively. This methodology has potential applications as ageneric tool to follow the sintering phenomenon and process kinetics at anystage during induration.
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| 30. |
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| 31. |
- Lestinsky, M., et al.
(författare)
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CRYRING@ESR: present status and future research
- 2015
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Ingår i: Physica Scripta. - : IOP Publishing. - 1402-4896 .- 0031-8949. ; 2015:T166
-
Konferensbidrag (refereegranskat)abstract
- The former storage ring CRYRING has been shipped from the Manne Siegbahn Laboratory in Stockholm to Darmstadt as a Swedish in-kind contribution to FAIR. At its new location downstream of ESR all ion species presently accessible in ESR can be transferred to CRYRING, in which ions with rigidities between 1.44 and 0.054 Tm can be stored. The original Swedish layout has been modified by reconfiguring the sequence of straight sections and by slightly increasing the circumference to ESR/2. Ions can be injected from ESR or from an independent 300 keV/u RFQ test injector. The instrumentation of the ring includes an RF drift tube system for acceleration and deceleration (1 T s(-1), with a possibility for an upgrade to 7 T s(-1)), electron cooling, a free experimental section, and both fast and slow extraction of ions. We report on the present progress of this project, give a prospective timeline, and summarize the new research which will be enabled by this project. First beam for commissioning of the storage ring is expected for 2015, final bakeout to restore ultrahigh vacuum conditions in 2016 and ion beams injected through ESR in similar to 2017.
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| 32. |
- Lestinsky, M., et al.
(författare)
-
Physics book: CRYRING@ESR
- 2016
-
Ingår i: European Physical Journal: Special Topics. - : Springer Science and Business Media LLC. - 1951-6401 .- 1951-6355. ; 225:5, s. 797-882
-
Forskningsöversikt (refereegranskat)abstract
- The exploration of the unique properties of stored and cooled beams of highly-charged ions as provided by heavy-ion storage rings has opened novel and fascinating research opportunities in the realm of atomic and nuclear physics research. Since the late 1980s, pioneering work has been performed at the CRYRING at Stockholm (Abrahamsson et al. 1993) and at the Test Storage Ring (TSR) at Heidelberg (Baumann et al. 1988). For the heaviest ions in the highest charge-states, a real quantum jump was achieved in the early 1990s by the commissioning of the Experimental Storage Ring (ESR) at GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt (Franzke 1987) where challenging experiments on the electron dynamics in the strong field regime as well as nuclear physics studies on exotic nuclei and at the borderline to atomic physics were performed. Meanwhile also at Lanzhou a heavy-ion storage ring has been taken in operation, exploiting the unique research opportunities in particular for medium-heavy ions and exotic nuclei (Xia et al. 2002).
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| 33. |
- Lundström, Erik
(författare)
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Modelling of fatigue crack propagation in Inconel 718 under hold time conditions
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis an investigation and modelling of the fatigue crack propagation in the nickel based superalloy Inconel 718, with a special emphasis on the effect of hold times, is presented. The modelling work has been concentrated on describing the hold time fatigue crack propagation by using the concept of a damaged zone in front of the crack tip, which is believed to have a lowered resistance against crack propagation.The modelling framework is built on physically motivated parameters, which are all easy to calibrate through one specially designed test type. Later evaluation through many experimental tests has also shown that the model is capable, within reasonable scatter level to predict, the hold time fatigue crack propagation for many different temperatures and loading conditions. Further evaluation of a complex flight spectrum, with the incorporation of crack closure within the model, was also predicted with a satisfying result.This thesis is divided into two parts. First, a background and a somewhat deeper discussion of the modelling of fatigue crack growth under hold time conditions is presented. The second part consists of ve appended papers, which describe the work completed so far in the project.
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| 34. |
- Lööv, Camilla, 1982-, et al.
(författare)
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Slow degradation in phagocytic astrocytes can be enhanced by lysosomal acidification
- 2015
-
Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 63:11, s. 1997-2009
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Tidskriftsartikel (refereegranskat)abstract
- Inefficient lysosomal degradation is central in the development of various brain disorders, but the underlying mechanisms and the involvement of different cell types remains elusive. We have previously shown that astrocytes effectively engulf dead cells, but then store, rather than degrade the ingested material. In the present study we identify reasons for the slow digestion and ways to accelerate degradation in primary astrocytes. Our results show that actin-rings surround the phagosomes for long periods of time, which physically inhibit the phago-lysosome fusion. Furthermore, astrocytes express high levels of Rab27a, a protein known to reduce the acidity of lysosomes by Nox2 recruitment, in order to preserve antigens for presentation. We found that Nox2 colocalizes with the ingested material, indicating that it may influence antigen processing also in astrocytes, as they express MHC class II. By inducing long-time acidification of astrocytic lysosomes using acidic nanoparticles, we could increase the digestion of astrocyte-ingested, dead cells. The degradation was, however, normalized over time, indicating that inhibitory pathways are up-regulated in response to the enhanced acidification.
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| 35. |
- Monazzma, Azita, et al.
(författare)
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Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring
- 2006
-
Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 6, s. 6-
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer.MethodsThe response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.ResultsThe effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.No effect of Imatinib was observed.ConclusionMTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.
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| 36. |
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| 37. |
- Olsson-Strömberg, Ulla, et al.
(författare)
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Imatinib activity in vitro in tumor cells from patients with chronic myeloid leukemia in chronic phase and blast crisis
- 2006
-
Ingår i: Anti-Cancer Drugs. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4973 .- 1473-5741. ; 17:6, s. 631-639
-
Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.
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| 38. |
- Olsson-Strömberg, Ulla, et al.
(författare)
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Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph plus ALL receiving dasatinib
- 2010
-
Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 85:5, s. 399-404
-
Tidskriftsartikel (refereegranskat)abstract
- As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.
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| 39. |
- Olsson-Strömberg, Ulla, et al.
(författare)
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Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase
- 2006
-
Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 47:9, s. 1768-73
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.
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| 40. |
- Padula, William V., et al.
(författare)
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Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States
- 2016
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 108:7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinibfirst incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.
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| 41. |
- Qvarnström, Fredrik, et al.
(författare)
-
Double strand break induction and kinetics indicate preserved hypersensitivity in keratinocytes to subtherapeutic doses for 7weeks of radiotherapy
- 2017
-
Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 122:1, s. 163-169
-
Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Previously we reported that hyper-radiosensitivity (HRS) was evidenced by quantifying DNA double strand break (DSB) foci in epidermis biopsies collected after delivering radiotherapeutic one and five dose fractions. The aim of this study was to determine whether HRS was preserved throughout a 7-week radiotherapy treatment, and also to examine the rate of foci decline and foci persistence between dose fractions. Materials and methods 42 patients with prostate cancer received 7-week fractionated radiotherapy treatment (RT) with daily dose fractions of 0.05–1.10Gy to the skin. Before RT, and at several times throughout treatment, skin biopsies (n=452) were collected at 30min, and 2, 3, 24, and 72h after dose fractions. DSB-foci markers, γH2AX and 53BP1, were labelled in epidermal keratinocytes with immunofluorescence and immunohistochemical staining. Foci were counted both with digital image analysis and manually. Results HRS in keratinocytes was evidenced by the dose–response relationships of DSB foci, observed throughout the treatment course, independent of sampling time and quantification method. Foci observed at 24h after dose fractions indicated considerable DSB persistence. Accordingly, foci significantly accumulated after 5 consecutive dose fractions. For doses below 0.3Gy, persistent foci could be observed even at 72h after damage induction. A comparison of γH2AX and 53BP1 quantifications in double-stained biopsies showed similar HRS dose–response relationships. Conclusions These results represented the first evidence of preserved HRS, assessed by γH2AX- and 53BP1-labelled DSB foci, throughout a 7-week treatment course with daily repeated subtherapeutic dose fractions. © 2016 Elsevier Ireland Ltd
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| 42. |
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| 43. |
- Qvarnström, Olov Fredrik, et al.
(författare)
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DNA double strand break quantification in skin biopsies.
- 2004
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Ingår i: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. - : Elsevier BV. - 0167-8140. ; 72:3, s. 311-7
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Following induction of double strand breaks the histone H2AX is rapidly phosphorylated at regions flanking the breaks resulting in nuclear gamma H2AX foci. The purpose of this study was to use this endogenous signalling system to quantify the in vivo response to radiation in normal tissue. PATIENTS AND METHODS: Skin biopsies were taken from prostate cancer patients undergoing radiotherapy with a curative intent. Biopsies were taken at locations corresponding to 5 different doses in the range below 1.1 Gy per fraction. Biopsies were taken from patients 30 min following the first fraction and then once again following the fraction given after the first weekend break in the treatment course. The DNA double strand breaks were visualised as gamma H2AX foci using immunohistochemistry. Images were acquired using a CCD-camera and a fluorescence microscope and the gamma H2AX foci were quantified using digital image analysis including the basic procedures of top-hat transformation, threshold setting and labelling. RESULTS: Repeated assessments of the biopsies showed a high reproducibility in quantifying the number of foci per DNA area of the nucleated cells in epidermis. The reproducibility was equally good for the two biopsy occasions. A linear dose response was observed for the epidermis in the dose region 0-1 Gy. CONCLUSIONS: We have established a method to measure the relative amount of DNA double strand breaks by detecting gamma H2AX foci in patients exposed to radiotherapy. The method provides a tool to study induction and repair of DNA double strand breaks and has the potential to predict individual radiosensitivity.
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| 44. |
- Qvarnström, O. Fredrik, et al.
(författare)
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Effects of affinity on binding of HER2-targeting Affibody molecules : Model experiments in breast cancer spheroids
- 2011
-
Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 39:2, s. 353-359
-
Tidskriftsartikel (refereegranskat)abstract
- Binding of a targeting agent in tumor tissue is influenced by many factors such as molecular weight, charge and affinity of the targeting agent and vascularization of the tumor. In this study, we analyzed tumor cell binding of three HER2-specific and radiolabeled Affibody molecules with different affinities. The Affibody molecules had affinities in the range of 0.12-3.8 nM. Cellular binding was analyzed, after 2 h of incubation, in tumor spheroids composed of BT474 breast cancer cells, which highly express HER2. Binding was, due to the binding-site barrier,limited to the outer 15 +/- 5 mu m rim of the spheroids, independent of affinity when the concentration of the substances was low. When the concentration was high, the binding site barrier was overcome and the binding occurred approximately 35 +/- 5 mu m into the spheroids for the two high affinity substances and 50 +/- 5 mu m for the low affinity substance. The lower affinity might allow for penetration into deeper regions due to less firm binding. We conclude that there is a binding site barrier within tumor spheroids which can be overcome by increased concentration of substance and modified by affinity.
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| 45. |
- Seppänen, Henri, et al.
(författare)
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One kilometer (1 km) electric solar wind sail tether produced automatically
- 2013
-
Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 84:9
-
Tidskriftsartikel (refereegranskat)abstract
- We produced a 1 km continuous piece of multifilament electric solar wind sail tether of μm-diameter aluminum wires using a custom made automatic tether factory. The tether comprising 90 704 bonds between 25 and 50 μm diameter wires is reeled onto a metal reel. The total mass of 1 km tether is 10 g. We reached a production rate of 70 m/24 h and a quality level of 1‰ loose bonds and 2‰ rebonded ones. We thus demonstrated that production of long electric solar wind sail tethers is possible and practical.
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| 46. |
- Shah, Furqan A., et al.
(författare)
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Laser-Modified Surface Enhances Osseointegration and Biomechanical Anchorage of Commercially Pure Titanium Implants for Bone-Anchored Hearing Systems.
- 2016
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
-
Tidskriftsartikel (refereegranskat)abstract
- Osseointegrated implants inserted in the temporal bone are a vital component of bone-anchored hearing systems (BAHS). Despite low implant failure levels, early loading protocols and simplified procedures necessitate the application of implants which promote bone formation, bone bonding and biomechanical stability. Here, screw-shaped, commercially pure titanium implants were selectively laser ablated within the thread valley using an Nd:YAG laser to produce a microtopography with a superimposed nanotexture and a thickened surface oxide layer. State-of-the-art machined implants served as controls. After eight weeks' implantation in rabbit tibiae, resonance frequency analysis (RFA) values increased from insertion to retrieval for both implant types, while removal torque (RTQ) measurements showed 153% higher biomechanical anchorage of the laser-modified implants. Comparably high bone area (BA) and bone-implant contact (BIC) were recorded for both implant types but with distinctly different failure patterns following biomechanical testing. Fracture lines appeared within the bone ~30-50 μm from the laser-modified surface, while separation occurred at the bone-implant interface for the machined surface. Strong correlations were found between RTQ and BIC and between RFA at retrieval and BA. In the endosteal threads, where all the bone had formed de novo, the extracellular matrix composition, the mineralised bone area and osteocyte densities were comparable for the two types of implant. Using resin cast etching, osteocyte canaliculi were observed directly approaching the laser-modified implant surface. Transmission electron microscopy showed canaliculi in close proximity to the laser-modified surface, in addition to a highly ordered arrangement of collagen fibrils aligned parallel to the implant surface contour. It is concluded that the physico-chemical surface properties of laser-modified surfaces (thicker oxide, micro- and nanoscale texture) promote bone bonding which may be of benefit in situations where large demands are imposed on biomechanically stable interfaces, such as in early loading and in compromised conditions.
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| 47. |
- Simonsson, Jesper, et al.
(författare)
-
Observability and Chaos Engineering on System Calls for Containerized Applications in Docker
- 2021
-
Ingår i: Future generations computer systems. - : Elsevier BV. - 0167-739X .- 1872-7115. ; 122, s. 117-129
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper, we present a novel fault injection system called ChaosOrca for system calls in containerized applications. ChaosOrca aims at evaluating a given application's self-protection capability with respect to system call errors. The unique feature of ChaosOrca is that it conducts experiments under production-like workload without instrumenting the application. We exhaustively analyze all kinds of system calls and utilize different levels of monitoring techniques to reason about the behaviour under perturbation. We evaluate ChaosOrca on three real-world applications: a file transfer client, a reverse proxy server and a micro-service oriented web application. Our results show that it is promising to detect weaknesses of resilience mechanisms related to system calls issues.
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| 48. |
- Simonsson, Martin, et al.
(författare)
-
Epidermal keratinocyte loss in response to daily 2 Gy fractions for 5 weeks of radiotherapy is associated with DSB-foci, growth arrest, apoptosis and lack of accelerated repopulation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and purpose: Tissue-sparing due to repopulation is expected to occur in epithelial cell populations during a course of fractionated radiotherapy (RT). Recently, we established, in the clinical setting of RT, the dose response relationship of subtherapeutic doses in terms of epidermal keratinocyte loss in the basal layer throughout 7 weeks of RT. Surprisingly, in the case of daily dose fractions of 1.10Gy, the keratinocyte loss per dose unit increases over the last 4 weeks of the treatment period rather than being constant or decreasing. The aim of the present study is to elaborate on the issue of germinal keratinocyte response to daily dose fractions of 2.0Gy for 5 weeks. Here, we present assessments of keratinocyte loss, DSB foci, growth arrest, mitosis and apoptosis using methods earlier described by us. Materials and Methods: In total 240 skin punch biopsies, collected from 31 breast cancer patients, before, during and after postmastectomy radiotherapy given to the thoracic wall with daily 2.0Gy fractions for 5 weeks, were investigated. The dose response for basal keratinocyte density of the interfollicular epidermis was determined. The DNA damage response of keratinocytes was studied by immunostaining for molecular markers of DNA DSBs, growth arrest, mitosis and cell death using 53BP1, p21, phospho-H3 and γH2AX (apoptosis), respectively. The stainings of keratinocytes were counted manually or by digital image analysis. Results: The dose-response relationship for the loss of basal keratinocytes over 5 weeks of RT revealed a biphasic shape. An initial radioresistant phase was followed by an increase in radiosensitivity in the second part of RT. The rate of keratinocyte loss reflected the significant changes determined by 53BP1 and γH2AX foci 30 minutes after dose fractions over the treatment period. The highest induction of DSB foci per cell was observed towards the end of treatment. The increase in the fraction of p21 stained cells was also more prominent during the second half of the treatment as compared to the first period of RT. The apoptotic frequency was generally low but increased dramatically towards the end of RT. The mitotic cell number was significantly suppressed over 5 weeks, and did not recover during the weekend treatment-gaps. Notably, the mitotic rate increased more than threefold compared to unexposed skin, 2 weeks after the end of RT, followed by a rapid decline one week later. Conclusion: The dose response for germinal keratinocyte loss as a result of daily dose fractions of 2.0Gy over 5 weeks treatment deviates significantly from an exponential curve fit. The effectiveness of each dose fraction was less in the first half of the treatment when compared with the second half. No accelerated repopulation could be revealed over the 5 weeks, but was evident after completion of radiotherapy. The changes in keratinocyte response were associated with changes in induction of DSB foci and p21 protein expression, as well as apoptotic events over the treatment period. In particular, we highlight the existence of pre-mitotic apoptosis, which increased significantly towards the end of 5 weeks RT. These findings suggest that it is necessary to reconsider the current conceptions regarding DNA repair, cell-cycle redistribution and repopulation of normal epithelial cells to a long-lasting courses of fractionated radiotherapy.
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- Simonsson, Martin, et al.
(författare)
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Low-dose hypersensitive gammaH2AX response and infrequent apoptosis in epidermis from radiotherapy patients.
- 2008
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Ingår i: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 88:3, s. 388-97
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: A low-dose hypersensitivity to radiation can be observed in vitro for many human cell types in terms of increased cell kill per dose unit for doses below 0.5Gy. Quantification of the double-strand break marker gammaH2AX in samples taken in clinical radiotherapy practice has the potential to provide important information about how induction and repair of severe DNA damage and apoptosis are linked to low-dose hypersensitivity. MATERIAL AND METHODS: The effects of exposure to low doses (0.05-1.1Gy) were investigated in skin biopsies taken from prostate cancer patients undergoing the first week of radiotherapy. gammaH2AX foci and apoptotic cells were visualised by immunohistochemistry and quantified by image analysis. RESULTS: The gammaH2AX foci pattern in biopsies taken 30min after a single fraction revealed a low-dose hypersensitivity below 0.3Gy (p=0.0009). The result was consistent for repeated fractions (p=0.00001). No decrease in foci numbers could be detected when comparing biopsies taken 30min and 2h after single fractions of 0.4 and 1.2Gy. The result was consistent for repeated fractions. Only 43 of 168,000 cells in total were identified as apoptotic, yet a dose dependency could be detected after 1week of radiotherapy (p=0.003). CONCLUSIONS: We describe a method based on gammaH2AX to study DNA damage response and apoptosis in a clinical setting. A gammaH2AX hypersensitive response to low doses can be observed in epidermal skin, already 30min following delivered fraction. A very low frequency of apoptosis in normal epithelium suggests that this effect is not an important part of the in vivo response to low doses.
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