| 1. |
- Elo, Robin, 1988-
(författare)
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Protective Tribofilms on Combustion Engine Valves
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inside the complex machinery of modern heavy-duty engines, the sealing surfaces of the valve and valve seat insert have to endure. Right next to the combustion, temperatures are high and high pressure deforms the components, causing a small relative motion in the interface. The wear rate of the surfaces has to be extremely low; in total every valve opens and closes up to a billion times. The minimal wear rate is achieved thanks to the formation of protective tribofilms on the surfaces, originating from oil residues that reach the surfaces - even though these are not intentionally lubricated. The increasing demands on service life, fuel efficiency and clean combustion, lead to changes that may harm the formation of tribofilms, which would lead to dramatically reduced service lives of the valves. This calls for an improved understanding of the formation of tribofilms and how their protective effects can be promoted.The best protective effect is provided by tribofilms formed from engine oil additives. This is not a typical lubricating effect, but protection by formation and replenishment of a solid coating. Oils without additives cannot form solid films that offer the same protection. Tribofilms are formed from oil residue particles that land, agglomerate and so gradually cover the surfaces. Once covered, the surfaces stay protected relatively long also if no new residues reach the surface. In fact, the tribofilms have a higher wear resistance than do the component surfaces. If the tribofilms become worn off, the underlying surfaces wear quickly, but as long as new residues reach the surfaces, the tribofilms can rebuild and maintain the wear protection indefinitely.This tribofilm formation and endurance can be promoted by texturing the surfaces. A texture can improve the amount of oil residues captured and their surface coverage, reducing random occurrence of wear and the demand for new residues to maintain the tribofilm. The tribofilm formation is also affected by the additive content of the engine oil, where especially high sulfur content is found to promote tribofilm coverage. A custom engine oil with high additive content could be used for efficient tribofilm formation during running-in of engines.
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| 2. |
- Garousi, Javad, et al.
(författare)
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ADAPT, a Novel Scaffold Protein-Based Probe for Radionuclide Imaging of Molecular Targets That Are Expressed in Disseminated Cancers
- 2015
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Ingår i: Cancer Research. - : American Association for Cancer Research Inc.. - 0008-5472 .- 1538-7445. ; 75:20, s. 4364-4371
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Tidskriftsartikel (refereegranskat)abstract
- Small engineered scaffold proteins have attracted attention as probes for radionuclide-based molecular imaging. One class of these imaging probes, termed ABD-Derived Affinity Proteins (ADAPT), has been created using the albumin-binding domain (ABD) of streptococcal protein G as a stable protein scaffold. In this study, we report the development of a clinical lead probe termed ADAPT6 that binds HER2, an oncoprotein overexpressed in many breast cancers that serves as a theranostic biomarker for several approved targeting therapies. Surface-exposed amino acids of ABD were randomized to create a combinatorial library enabling selection of high-affinity binders to various proteins. Furthermore, ABD was engineered to enable rapid purification, to eradicate its binding to albumin, and to enable rapid blood clearance. Incorporation of a unique cysteine allowed site-specific conjugation to a maleimido derivative of a DOTA chelator, enabling radionuclide labeling, In-111 for SPECT imaging and Ga-68 for PET imaging. Pharmacologic studies in mice demonstrated that the fully engineered molecule In-111/Ga-68-DOTA(HE) 3-ADAPT6 was specifically bound and taken up by HER2-expressing tumors, with a high tumor-to-normal tissue ratio in xenograft models of human cancer. Unbound tracer underwent rapid renal clearance followed by high renal reabsorption. HER2-expressing xenografts were visualized by gamma-camera or PET at 1 hour after infusion. PET experiments demonstrated feasibility for discrimination of xenografts with high or low HER2 expression. Our results offer a preclinical proof of concept for the use of ADAPT probes for noninvasive in vivo imaging.
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| 3. |
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| 4. |
- Hoffmann, Mikael, et al.
(författare)
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Changes in women’s attitudes towards and use of hormone therapy after HERS and WHI
- 2005
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Ingår i: Maturitas. - : Elsevier. - 0378-5122 .- 1873-4111. ; 52:1, s. 11-17
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Tidskriftsartikel (refereegranskat)abstract
- Objectives:To assess changes in women's attitudes towards risk and benefits of, and use of hormone treatment in the menopausal transition (HT) before and after Heart and Estrogen/Progestin Replacement Study (HERS) and the oestrogen and progestin trial of Women's Health Initiative (WHI).Methods:Postal questionnaires to all women 53 and 54 years of age in a Swedish community in 1999 (n = 1.760) and 2003 (n = 1.733). Data on sales of HT were collected from the database of the National Corporation of Swedish Pharmacies.Results:The fraction of women reporting current use of HT fell from 40.5 to 25.3% (p < 0.001, χ2-test) both by fewer women starting and more women discontinuing treatment. This corresponded to a decrease in dispensation of HT in Linköping and nationwide for the same age group. The fraction of women who had tried complementary treatment for climacteric discomfort, increased from 9.6 to 18.1% for natural remedies (p < 0.001, χ2-test).Women perceived HT as more risky and less beneficial in 2003 as compared with 1999 (both p < 0.001, χ2-test). The most frequent source of information about HT during the last year before the 2003 questionnaire were newspaper or magazines (43.8%) and television or radio (31.7%).Conclusions:The decreased use of HT in the community correlated with pronounced changes in the attitudes towards HT. Media were a more frequent source of information than health care personnel. This indicates that media reports about major clinical studies might have influenced the use of HT among women.
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| 5. |
- Hoffmann, Mikael, et al.
(författare)
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Hormone replacement therapy in the menopause - structure and content of risk talk
- 2005
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Ingår i: Maturitas. - : Elsevier BV. - 0378-5122 .- 1873-4111. ; 50:1, s. 8-18
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate how risks and benefits of hormone replacement therapy (HRT) are communicated to women in clinical practice. To evaluate the usefulness of a risk classification based on context framing, i.e. whether the risk is discussed for one or several alternative treatments, and/or in the same context as possible benefits. Design: Analysis of structure and content of transcribed consultations (n=20) from first-time visits for discussion of climacteric discomfort and/or HRT with five physicians at three different out-patient clinics of gynecology. Results: All women received a prescription of HRT. An alternative to HRT was discussed in seven of the consultations. No decision aids were used. Risk discussion was dominated by the physicians giving information about long-time risk and benefits. The decision to prescribe was made either before the risk discussion was initiated, or before it was finished, in 8 of the 18 consultations where risk discussion was present. Risk classification according to context framing was performed and indicated use of different communication strategies by the physicians.Conclusions: The perspective of the physicians was mainly on prevention while the women were more focused on symptom alleviation. Each physician had a strategy of his/her own for the risk discussion. Thus, the major differences found between the consultations were between physicians, and not between the women. Risk discussion seemed to be aimed at motivating the woman to follow the physician’s decision rather than to help her participate in the decision-making process.
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| 6. |
- Hoffmann, Mikael, et al.
(författare)
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Risk communication in consultations about hormone therapy in the menopause – concordance in risk assessment and framing due to the context
- 2006
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Ingår i: Climacteric. - : Informa UK Limited. - 1369-7137 .- 1473-0804. ; 9:5, s. 347-354
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIt is important for the physician and the patient to have a mutual understanding of the possible consequences of different treatment alternatives in order to achieve a partnership in decision making.ObjectiveThe aim of this study was to explore to which degree first-time consultations for discussion of climacteric discomfort achieved shared understanding of the risks and benefits associated with hormone therapy in the menopausal transition (HT).MethodsAnalysis of structure and content of transcribed consultations (n=20), and follow-up interviews of the women (n=19 pairs of consultations and interviews), from first-time visits for discussion of climacteric discomfort and/or HT with five physicians at three different out-patient clinics of gynaecology in Sweden.ResultsFour distinctively different interpretations of risk, depending on whether or not benefits were discussed in the same context, emerged from the analysis. On average 5 advantages (range 0-11) and 2 (0-3) disadvantages were mentioned during the consultations. In the interviews the women expressed on average 4 advantages (0-7) and 1 disadvantage (0-3). There were major variations between advantages and disadvantages expressed in the consultation and the following interview.ConclusionEven though the consultations scored high in patient involvement, the information in most consultations was not structured in a way that made it possible to achieve a shared or an informed decision making.
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| 7. |
- Hoffmann, Mikael, et al.
(författare)
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Risk talk : rhetorical strategies in consultations on hormone replacement therap
- 2005
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Ingår i: Health, Risk and Society. - Hants, UK : Carfax Publishing. - 1369-8575 .- 1469-8331. ; 5:2, s. 139-154
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Tidskriftsartikel (refereegranskat)abstract
- When analysing risk discussions in medical settings it is important to consider the specific activity type. In this qualitative study 20 first-time consultations by healthy women regarding hormone replacement therapy (HRT) in the menopause the risk discussion is asymmetrical with the doctors dominating. Despite being set up as a specific opportunity for women in the menopause to discuss problems and risks, it comes forth as a decision-making activity in a traditional medical setting. The consultations fulfil to a high extent the demands for informed decision making, but the risk discussions are recontextualised into a cost-benefit discourse with a typical implicit quantitative bias. The doctors use several different rhetorical strategies such as positive introduction of HRT, embedding drawbacks in positive introductions and/or exits thereby diminishing them. The word risk is avoided to a considerable extent and the term 'drawbacks' is used instead. The most obvious strategy is to move from the woman's symptoms to aspects of prevention, thus changing the discussion from the menopause and different strategies to cope with menopausal problems into a medically oriented discussion of pharmacological treatment alternatives. The 'change of life' in these talks is entirely conceptualised within a 'medical model'.
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| 8. |
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| 9. |
- Jaen Ortega, A. A., et al.
(författare)
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On Understanding the Role of Exoskeleton Robots in Hand Rehabilitation : A Brief Review
- 2022
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Ingår i: Proceedings - 2022 8th International Engineering, Sciences and Technology Conference, IESTEC 2022. - : Institute of Electrical and Electronics Engineers Inc.. - 9781665498432 ; , s. 432-439
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Konferensbidrag (refereegranskat)abstract
- Hand rehabilitation has been widely studied since it affects the life quality and independence of those affected. Hand impairment can be caused by several conditions, among them strokes and other cerebrovascular accidents, affecting the capabilities of those who survive them in performing the activities of daily living (ADL). Rehabilitation seeks to restore the ability of a person to perform these crucial ADL. There is a current trend in using robotic rehabilitation and other industry 4.0 tools since it can provide a safe, intensive, and task-oriented at a relatively low cost, which can be combined with other technologies such as virtual and augmented reality, BCI, haptics, and others. Moreover, it can provide accessibility in the face of current panoramas such as COVID-19. Hand exoskeleton robots are one of the most extended robotic devices for rehabilitation. However, a design adapted to the patient's needs is necessary to achieve their capability fully and succeed in rehabilitation. One of the main challenges is that several considerations and parameters affect these devices' design and the broad approaches that can be followed. This brief review aims to understand and empathize as a source of inspiration during the design process of hand exoskeleton robots for rehabilitation.
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| 10. |
- Järvstråt, Lotta, et al.
(författare)
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Use of hormone therapy in Swedish women aged 80 years or older
- 2015
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Ingår i: Menopause. - 1072-3714 .- 1530-0374. ; 22:3, s. 275-278
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Menopausal symptoms such as hot flashes and night sweats may persist for 10 to 20 years or even longer. Information about the extent to which older women use hormone therapy is limited. The aim of this study was to determine the use of hormone therapy in Swedish women aged 80 years or older.Methods: The study is based on national register data on dispensed drug prescriptions (ie, prescribed therapy that has been provided to individuals by pharmacies) for hormone therapy and local low-dose estrogens.Results: Of 310,923 Swedish women who were aged at least 80 years, 609 (0.2%) were new users of hormone therapy. A total of 2,361 women (0.8%) were current users of hormone therapy. The median duration of hormone therapy use in new users was 257 days (25th to 75th percentiles, 611-120 d). About one in six women aged 80 years or older had used local vaginal estrogen therapy for at least four 3-month periods. The drugs were mainly prescribed by gynecologists and general practitioners.Conclusions: Our results show that a number of women aged 80 years or older still use hormone therapy and that most women who started a new treatment period had only one or two dispensations despite the median duration of treatment being more than half a year. Because at least some of the women aged 80 years or older who used hormone therapy probably did so owing to persistent climacteric symptoms, vasomotor symptoms and hormone therapy are still relevant issues that need to be discussed when counseling women around and after age 80.
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| 11. |
- Kubyshkina, Elena, 1990-
(författare)
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Ab initio modelling of interfaces in nanocomposites for high voltage insulation
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dielectric nanocomposite materials have been experimentally proven to have properties that are beneficial in applications for efficient energy transport. However, today there are still no empirical models or rules that can predict the performance of a certain combination of materials in the nanocomposite, and there are also no definitive explanations of their dielectric behavior. A deeper understanding of the phenomena behind these materials' response to an applied electric field can open new possibilities for improvement of the insulating properties of nanocomposites.The goal of this work is to locate the key processes that are responsible for dielectric performance. The methodology of the study is based on ab initio technology, that relies solely on the knowledge of chemical and structural composition of the material. In this work, the charge-related properties of nanocomposite interfaces are studied. The primary material of the study is chosen to be polyethylene-based composite with magnesium oxide nanoparticles.The impact of the nanoparticle crystal surface termination and its silane treatment on the electronic structure of the interface between MgO and polyethylene are investigated here. Moreover, the effects of presence of carboxyl defect and water molecule near the interface are considered in this work as well.Based on the calculated electronic structure data, a model for charge dynamics is proposed. The model explains mechanisms for conductivity and space charge reduction in nanocomposites, but also predicts an increase in thermal stress and susceptibility for chemical defects. It is suggested here that the suppression mechanisms for space charge and conductivity in nanocomposites are inherently unstable and can also accelerate material aging.
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| 12. |
- Lindbo, Sarah, et al.
(författare)
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Influence of Histidine-Containing Tags on Biodistribution of Radiolabelled ADAPT-Based Imaging Probes
- 2015
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 42, s. S100-S100
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Tidskriftsartikel (refereegranskat)abstract
- Aim. ADAPTs are a class of small ( ∼ 5 kDa) robust scaffold proteins suitable as probes for radionuclide molecular imaging in vivo. The attachment of a histidine-containing tags to the scaffold proteins allows efficient purification by immobilized metal ion affinity chromatography (IMAC) and permits labelling with 99mTc(CO)3. Earlier, we have demonstrated that replacement of the hexahistidine (H6)-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HE3)-tag reduces hepatic uptake of radiolabelled affibody molecules. The same effect has been confirmed for other scaffold proteins, DARPins, and short peptides. The aim of this study was to evaluate effect of histidine-containing tag composition on biodistribution of ADAPTs. Material and methods. A series of anti-HER2 ADAPT6 probes having DEAVDANS lead sequence and H6- or HE3-tags at N-termini has been prepared. In two variants, maleimido derivative of DOTA was conjugated to a unique cysteine was incorporated at N-terminus. DOTA-C-HE3-ADAPT6 and DOTA-C-H6-ADAPT6 were labelled with 111In. HE3-ADAPT6 and H6-ADAPT6 were labelled with 99mTc(CO)3using IsoLink kit. Binding specificity, affinity, and cellular processing of new conjugates was evaluated using HER2-expressing SKOV-3 ovarian carcinoma cells. Biodistribution at 1,4 and 24 h p.i. was evaluated in normal NMRI mice. Tumour-targeting properties of the best 99mTc(CO) 3-labelled variant, 99mTc(CO)3-H6-ADAPT6 were evaluated in BALB/C nu/nu mice bearing SKOV-3 xenografts. Results. All radiolabeled ADAPTs demonstrated specific binding to SKOV-3 cells with affinities in the range of 1.1-2.8 nM. The internalization by SKOV-3 cells was slow. In vivo, all conjugates cleared rapidly from blood via kidneys with subsequent renal re-absorption. The hepatic uptake of 111In-DOTA-C-H6-ADAPT6 was slightly but significantly (p<0.05) higher that the uptake of 111In-DOTA-C-HE3-ADAPT6 at 1 h pi, but biodistribution was very similar at later time points. Surprisingly, the uptake of 99mTc(CO)3-HE3-ADAPT6 was significantly (p<0.05) higher than uptake of 99mTc(CO)3-H6-ADAPT6 in liver, blood, and bone at 1h p.i. At 4 h p.i., hepatic uptakes were equal, but 99mTc(CO)3-H6-ADAPT6 provided lower uptake in blood and bone. 99mTc(CO)3-H6-ADAPT6 demonstrated high (19? 3 %ID/g at 4 h p.i.) and specific tumour uptake. Tumour-to-blood and tumour-to-liver ratios were 102? 29 and 12? 3, respectively. Conclusion. Influence of histidine-containing tag on biodistribution of scaffold proteins depends on composition of a scaffold protein and might differ appreciably. This should be take into account in molecular design of imaging probes based on engineered scaffold proteins
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| 13. |
- Lindbo, Sarah, et al.
(författare)
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Influence of Histidine-Containing Tags on the Biodistribution of ADAPT Scaffold Proteins.
- 2016
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Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 27:3, s. 716-726
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Tidskriftsartikel (refereegranskat)abstract
- Engineered scaffold proteins (ESP) are high-affinity binders that can be used as probes for radionuclide imaging. Histidine-containing tags enable both efficient purification of ESP and radiolabeling with (99m)Tc(CO)3. Earlier studies demonstrated that the use of a histidine-glutamate-histidine-glutamate-histidine-glutamate (HE)3-tag instead of the commonly used hexahistidine (H6)-tag reduces hepatic uptake of radiolabeled ESP and short peptides. Here, we investigated the influence of histidine-containing tags on the biodistribution of a novel type of ESP, ADAPTs. A series of anti-HER2 ADAPT probes having H6- or (HE)3-tags in the N-termini were prepared. The constructs, (HE)3-ADAPT6 and H6-ADAPT6, were labeled with two different nuclides, (99m)Tc or (111)In. The labeling with (99m)Tc(CO)3 utilized the histidine-containing tags, while (111)In was attached through a maleimido derivative of DOTA conjugated to the N-terminus. For (111)In-labeled ADAPTs, the use of (HE)3 provided a significantly (p < 0.05) lower hepatic uptake at 1 h after injection, but there was no significant difference in hepatic uptake of (111)In-(HE)3-ADAPT6 and H6-ADAPT6 at later time points. Interestingly, in the case of (99m)Tc, (99m)Tc(CO)3-H6-ADAPT6 provided significantly (p < 0.05) lower uptake in a number of normal tissues and was more suitable as an imaging probe. Thus, the influence of histidine-containing tags on the biodistribution of the novel ADAPT scaffold proteins was different compared to its influence on other ESPs studied so far. Apparently, the effect of a histidine-containing tag on the biodistribution is highly dependent on the scaffold composition of the ESP.
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| 14. |
- Lindh-Åstrand, Lotta, et al.
(författare)
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Attitudes towards the menopause and hormone therapy over the turn of the century
- 2007
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Ingår i: Maturitas. - : Institutionen för klinisk och experimentell medicin. - 0378-5122 .- 1873-4111. ; 56:1, s. 12-20
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess attitudes and beliefs about the menopausal transition in a population of peri- and postmenopausal women, and if these attitudes differed before and after publication of studies on risks and benefits with hormone therapy (HT). Material and methods: In 1999 and 2003 all women aged 53 and 54 years in the community of Linköping, Sweden, were sent a questionnaire about use of HT, menopausal status and attitudes regarding menopause and HT. Results: Most women regarded menopause as a natural process characterized by both hormonal deficiency and aging and these views did not differ between 1999 and 2003. A majority of women thought that significant climacteric symptoms were a good reason to use HT, but not that women without symptoms should use HT. The fraction of women who supported HT use was, however, significantly lower in 2003 than in 1999. Most women agreed that menopause leads to increased freedom and that it is a relief not to have to think about contraception and pregnancies. Conclusions: Most Swedish women had a mainly biological view on menopause but nevertheless they thought that only women with climacteric symptoms should use HT. Women’s attitudes towards HT have changed after recent reports on risks from long-term use of HT whereas the attitudes towards the menopausal transition were stable. Other factors than attitudes towards menopause affect women’s actual use of HT. Probably women’s and health care provider’s apprehension of the risk-benefit balance of HT use is one such factor.
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| 15. |
- Lindh-Åstrand, Lotta, et al.
(författare)
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Hormone therapy might be underutilized in women with early menopause.
- 2015
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 30:4, s. 848-852
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION Are Swedish women age 40–44 years with assumed early menopause ‘undertreated’ by hormone therapy (HT)?SUMMARY ANSWER Many women with probable early menopause discontinue their HT after a short period of time. Thus, they fail to complete the recommended replacement up to age 51–52 years, the average age of menopause.WHAT IS KNOWN ALREADY Spontaneous early menopause occurs in ∼5% of women age 40–45 years. Regardless of the cause, women who experience hormonal menopause due to bilateral oophorectomy before the median age of spontaneous menopause are at increased risk of cardiovascular disease, neurological disease, osteoporosis, psychiatric illness and even death.STUDY DESIGN, SIZE, DURATION The study is descriptive, and epidemiological and was based on the use of national registers of dispensed drug prescriptions (HT) linking registers from the National Board of Health and Welfare and Statistics Sweden from 1 July 2005 until 31 December 2011.PARTICIPANTS/MATERIALS, SETTING, METHODS The study population consisted of 310 404 women, 40–44 years old on 31 December 2005 who were followed from 1 July 2005 until 31 December 2011.MAIN RESULTS AND THE ROLE OF CHANCE Only 0.9% of women 40–44 years old started HT during the study period. A majority of these women used HT <1 year.LIMITATIONS, REASONS FOR CAUTION We do not know the indications that led to the prescription of HT but assume that early onset of menopause was the main reason. Because of the study design—making a retrospective study of registers—we can only speculate on the reasons for most of the women in this group discontinuing HT. Another limitation of this study is that we have a rather short observation time. However, we have up to now only been able to collect and combine the data since July 2005.WIDER IMPLICATIONS OF THE FINDINGS As the occurrence of spontaneous early menopause in women age 40–45 is reported to be ∼5%, the fact that <1% of Swedish women age 40–44 are prescribed HT, and can be shown also to have had the medication dispensed at a pharmacy suggests an unexpectedly low treatment rate. Some women with early menopause may have used combined contraceptives as supplementation therapy, but in Sweden HT is the recommended treatment for early menopause so any such women are not following this recommendation. Women who experience early menopause are at increased risk for overall morbidity and mortality, and can expect to benefit from HT until they have reached at least the median age of spontaneous menopause. It is therefore important to individualize the information given these women and to convey new knowledge in this area to gynaecologists and physicians in general as well as the recommendation that women in this group continue HT at least until the average age for spontaneous menopause is reached.
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| 16. |
- Lindh-Åstrand, Lotta, et al.
(författare)
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Hot flushes, hormone therapy and alternative treatments: 30 years of experience from Sweden
- 2015
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Ingår i: Climacteric. - : Informa Healthcare. - 1369-7137 .- 1473-0804. ; 18:1, s. 53-62
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The use of hormone therapy (HT) for hot flushes has changed dramatically over the past five decades. In this cross-sectional questionnaire study, the aim was to describe the use of HT and alternative treatments and to study the frequency of hot flushes. A further aim was to compare data from the present questionnaire with data from previous studies made in the same geographic area. Method A questionnaire was sent to a random sample of 2000 women aged 47-56 years living in Ostergotland County, Sweden. The results were compared with findings from previous studies regarding use of HT, alternative treatment and hot flushes, and the number of HT prescriptions dispensed during the corresponding time using data derived from the Swedish Prescribed Drug Registry. Results The response rate was 66%. Six percent used HT, in line with prevalence data from the Swedish Prescribed Drug Registry. Alternative treatments were used by 10%. About 70% of postmenopausal women reported flushes and almost one-third of those with flushes stated that they would be positive to HT if therapy could be shown to be harmless, a view more often stated by women with severe complaints of hot flushes (67%). Conclusion The use of HT and alternative treatments is low and many women suffer from flushes that could be treated. Women considered their knowledge of the climacteric period and treatment options as insufficient. Individualized information should be given and women with significant climacteric complaints, without contraindications, should be given the opportunity to try HT.
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| 17. |
- Lindh-Åstrand, Lotta, 1958-, et al.
(författare)
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Knowledge of reproductive physiology and hormone therapy in 53- to 54-year-old Swedish women
- 2007
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Ingår i: Menopause. - : Raven Press. - 1072-3714 .- 1530-0374. ; 14:6, s. 1039-1046
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate knowledge of hormone therapy (HT), reproductive physiology, and menopause in a population of 53- to 54-year-old women. Further aims were to determine whether the knowledge differed between users and nonusers of HT and between groups with different levels of education.Design: In 2003, all 53- and 54-year-old women (N = 1,733) in Linkoping, Sweden, were sent a questionnaire containing questions about reproductive physiology related to menopause and HT. Answers from 73% of the women were analyzed.Results: Swedish women had limited knowledge of HT, reproductive physiology, and menopause irrespective of HT use or educational level. Most of the women knew that hot flashes are common around menopause and decreasing estrogen production causes the menopause. They knew little about the effects of progestagens and the effects of HT on fertility. Women with low educational level were more likely to answer the questions by stating that they were unsure than did women with high educational level. Ever-users of HT knew more than never-users about risks and benefits of HT in relation to breast cancer and osteoporosis, and ever-users thought that the risks of thrombosis and myocardial infarction were lower than did never-users.Conclusions: Women need improved knowledge of the risks and benefits of HT as well as education about the reproductive system around menopause. This would probably better support and empower women to manage an important period of their lives.
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| 18. |
- Lindh Åstrand, Lotta, et al.
(författare)
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Use of hormone therapy (HT) among Swedish women with contraindications - A pharmacoepidemiological cohort study
- 2019
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Ingår i: Maturitas. - : ELSEVIER IRELAND LTD. - 0378-5122 .- 1873-4111. ; 123, s. 55-60
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To assess how women in Sweden with breast cancer (BC), endometrial cancer (EC), and/or pulmonary embolism (PE) were dispensed menopausal hormone therapy (HT). Study design: A retrospective study of Swedish women aged 40 years or more on 31 December 2005 (n = 2,863,643), followed through to December 2011. The study analysed three mandatory national healthcare registries: the Swedish Prescribed Drug Register, the National Inpatient Register and the Cancer Register. New users were defined as having a first dispensation after at least a 9-month break, and thus were possible to identify from April 2006. New users with at least one of the diagnoses BC, EC or PE before the first dispensation were classified as having a relative or absolute contraindication for HT. Main outcome measures: The relative risks of having HT dispensed after being diagnosed with BC, EC and/or PE. Results: In total, 171,714 women had at least one of the diagnoses BC, EC or PE. The relative risk of having hormone therapy dispensed (current and new users) after being diagnosed with any of the diagnoses was significantly lower (PE, IRR 0.11, 95% CI 0.10-0.12;/ BC, IRR 0.12, 95% CI 0.11-0.13; EC, IRR 0.43, CI 0.40-0.46) than for women without these diagnoses. Conclusions: One in about 250 women started treatment with HT after being diagnosed with BC, PE or EC. Swedish prescribers seem to be well aware of the recommendations for HT use in women with contraindications. A few women, however, are prescribed HT despite having BC, EC or PE, possibly after careful evaluation of the risks and benefits and giving informed consent. Women with a history of PE were prescribed transdermal HT to a larger extent than women in general, in line with results from observational studies.
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| 19. |
- Lindh-Åstrand, Lotta, et al.
(författare)
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Vasomotor symptoms usually reappear after cessation of postmenopausal hormone therapy : a Swedish population-based study.
- 2009
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Ingår i: Menopause (New York, N.Y.). - : Ovid Technologies (Wolters Kluwer Health). - 1530-0374 .- 1072-3714.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:: The purpose of this study was to investigate the extent of reappearance of vasomotor symptoms after cessation of postmenopausal hormone therapy (HT) in women who started HT because of hot flashes. METHODS:: A cross-sectional postal survey was conducted. A validated questionnaire was sent to all women 53 to 54 years old living in Linköping, Sweden (n = 1,733), including questions about menopause, HT, and vasomotor symptoms. Pearson's chi test and logistic regression were used for statistical analyses. RESULTS:: Response rate after one reminder was 77.3%. After omitting incomplete answers, 72.9% remained for analysis. In all women, 319 (25.3%) were current users of HT, 242 (19.2%) were previous users, and 702 (55.6%) were never-users. Of the 242 previous users, 165 (69%) women stated that they had vasomotor symptoms before starting HT. Vasomotor symptoms recurred after cessation of HT in 143 (87%) of these 165 women. We found no significant difference in symptom recurrence in comparisons of the three groups based on usage of HT for 0 to 1, 2 to 4, or 5 years or more. CONCLUSIONS:: Most women who had vasomotor symptoms when they initiated HT reported recurrence of symptoms after cessation of HT (87%), although the flashes were usually reported to be less frequent and bothersome than they were before HT. Effective and safe treatment approaches for women with recurrence of vasomotor symptoms are needed.
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| 20. |
- Lindh-Åstrand, Lotta, et al.
(författare)
-
Vasomotor symptoms usually reappear after cessation of postmenopausal hormone therapy
- 2009
-
Ingår i: Menopause. - : Raven Press. - 1072-3714 .- 1530-0374. ; 16:6, s. 1213-1217
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The purpose of this study was to investigate the extent of reappearance of vasomotor symptoms after cessation of postmenopausal hormone therapy (HT) in women who started HT because of hot flashes.Methods: A cross-sectional postal survey was conducted. A validated questionnaire was sent to all women 53 to 54 years old living in Linkoping, Sweden (n = 1,733), including questions about menopause, HT, and vasomotor symptoms. Pearson's chi(2) test and logistic regression were used for statistical analyses.Results: Response rate after one reminder was 77.3%. After omitting incomplete answers, 72.9% remained for analysis. In all women, 319 (25.3%) were current users of HT, 242 (19.2%) were previous users, and 702 (55.6%) were never-users. Of the 242 previous users, 165 (69%) women stated that they had vasomotor symptoms before starting HT. Vasomotor symptoms recurred after cessation of HT in 143 (87%) of these 165 women. We found no significant difference in symptom recurrence in comparisons of the three groups based on usage of HT for 0 to 1, 2 to 4, or 5 years or more.Conclusions: Most women who had vasomotor symptoms when they initiated HT reported recurrence of symptoms after cessation of HT (87%), although the flashes were usually reported to be less frequent and bothersome than they were before HT. Effective and safe treatment approaches for women with recurrence of vasomotor symptoms are needed.
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| 21. |
- Lindh-Åstrand, Lotta, et al.
(författare)
-
Women's conception of the menopausal transition--a qualitative study.
- 2007
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Ingår i: Journal of clinical nursing. - : Wiley. - 0962-1067 .- 1365-2702. ; 16:3, s. 509-17
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: To explore, with a qualitative approach, whether the conception of menopause varies between women seeking medical advice because of climacteric symptoms and, if so, to describe these different conceptions. BACKGROUND: For many women, the menopausal transition is a troublesome period of life, often associated with decreased well-being and a number of symptoms. Besides the hormonal changes, many other factors such as psychological, sociological and lifestyle factors affect how women perceive their menopause. METHOD: Semi-structured interviews were held with 20 women after their first-time visits at outpatient clinics of gynaecology for discussion of climacteric symptoms. The interviews were audio-taped, transcribed and analysed using a phenomenographic approach. RESULTS: A wide variation of conceptions was revealed. Two main categories were identified including different physical changes with varying symptoms and both positive and negative psychological changes. The menopausal transition was also described as a natural process and as a developmental phase of life. CONCLUSION: Women's conceptions of the menopausal transition were individual and contained both physical and psychological symptoms but also expressed a more holistic view of the menopausal transition. The transition was described as a natural process affected by endocrine and life-style factors as well as by the psychosocial situation and by ageing per se. RELEVANCE TO CLINICAL PRACTICE: It is important that health care providers are aware of women's conceptions about the menopausal transition to be able to communicate optimally, support and empower middle-aged women in different health care situations and thereby optimize the result of care.
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| 22. |
- Nilsson, Lars, et al.
(författare)
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The molecular signature of MDS stem cells supports a stem-cell origin of 5q-myelodysplastic syndromes
- 2007
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:8, s. 3005-3014
-
Tidskriftsartikel (refereegranskat)abstract
- Global gene expression profiling of highly purified 5q-deleted CD34+CD38–Thy1+ cells in 5q– myelodysplastic syndromes (MDSs) supported that they might originate from and outcompete normal CD34+CD38–Thy1+ hematopoietic stem cells. Few but distinct differences in gene expression distinguished MDS and normal stem cells. Expression of BMI1, encoding a critical regulator of self-renewal, was up-regulated in 5q– stem cells. Whereas multiple previous MDS genetic screens failed to identify altered expression of the gene encoding the myeloid transcription factor CEBPA, stage-specific and extensive down-regulation of CEBPA was specifically observed in MDS progenitors. These studies establish the importance of molecular characterization of distinct stages of cancer stem and progenitor cells to enhance the resolution of stage-specific dysregulated gene expression.
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| 23. |
- Nilvebrant, Johan, et al.
(författare)
-
An orthogonal fusion tag for efficient protein purification
- 2014
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Ingår i: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1064-3745 .- 1940-6029. ; 1129, s. 205-210
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Tidskriftsartikel (refereegranskat)abstract
- Protein fusion tags are important tools in research when robust methods for protein purification and detection are required. In this chapter we present an efficient method for stringent protein purification. A small domain, denoted ABDz1, with affinity for both human serum albumin and Protein A has been developed. The purification tag is based on an albumin-binding domain from Streptococcal Protein G that was engineered to bind Protein A. The ABDz1-tag can be fused to any protein of choice and the purification can be performed using standard laboratory equipment. In this chapter a method for purification of ABDz1-tagged proteins using two successive affinity purification steps is described.
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| 24. |
- Nilvebrant, Johan, 1982-, et al.
(författare)
-
An orthogonal fusion tag for efficient protein purification
- 2021. - Volume 2178
-
Ingår i: Methods in Molecular Biology. - New York, NY : Springer Nature. ; , s. 159-166
-
Bokkapitel (refereegranskat)abstract
- In this chapter, we present an efficient method for stringent protein purification facilitated by a dual affinity tag referred to as ABDz1, which is based on a 5 kDa albumin-binding domain from Streptococcal Protein G. The small fusion tag enables an orthogonal affinity purification approach based on two successive and highly specific affinity purification steps. This approach is enabled by native binding of ABDz1 to human serum albumin and engineered binding to Staphylococcal Protein A, respectively. The ABDz1-tag can be fused to either terminus of a protein of interest and the purification steps can be carried out using standard laboratory equipment.
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| 25. |
- Nilvebrant, Johan, et al.
(författare)
-
Development and characterization of small bispecific albumin-binding domains with high affinity for ErbB3
- 2013
-
Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 70:20, s. 3973-3985
-
Tidskriftsartikel (refereegranskat)abstract
- Affinity proteins based on small scaffolds are currently emerging as alternatives to antibodies for therapy. Similarly to antibodies, they can be engineered to have high affinity for specific proteins. A potential problem with small proteins and peptides is their short in vivo circulation time, which might limit the therapeutic efficacy. To circumvent this issue, we have engineered bispecificity into an albumin-binding domain (ABD) derived from streptococcal Protein G. The inherent albumin binding was preserved while the opposite side of the molecule was randomized for selection of high-affinity binders. Here we present novel ABD variants with the ability to bind to the epidermal growth factor receptor 3 (ErbB3). Isolated candidates were shown to have an extraordinary thermal stability and affinity for ErbB3 in the nanomolar range. Importantly, they were also shown to retain their affinity to albumin, hence demonstrating that the intended strategy to engineer bispecific single-domain proteins against a tumor-associated receptor was successful. Moreover, competition assays revealed that the new binders could block the natural ligand Neuregulin-1 from binding to ErbB3, indicating a potential anti-proliferative effect. These new binders thus represent promising candidates for further development into ErbB3-signaling inhibitors, where the albumin interaction could result in prolonged in vivo half-life.
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| 26. |
- Nilvebrant, Johan, et al.
(författare)
-
Development and characterization of small bispecific three-helical ErbB3/albumin-binding domains aimed at therapeutic applications
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Affinity proteins based on small scaffolds are currently emerging as alternatives to antibodies for therapy. Similarly to antibodies, they can be engineered to have high affinity for specific proteins. A potential problem with small proteins and peptides is their short in vivo circulation time, which might limit the therapeutic efficacy. To circumvent this issue, we have engineered bispecificity into an albumin-binding domain (ABD) derived from streptococcal protein G. The inherent albumin binding was preserved while the opposite side of the molecule was randomized to create a flexible surface for selection of high-affinity binders. Here we present novel ABD-variants selected by phage display with the ability to bind to the epidermal growth factor receptor 3 (ErbB3). Isolated candidates were thoroughly characterized regarding affinity and stability. Importantly, they were shown to still have affinity to albumin, hence demonstrating that the intended strategy to engineer bispecific single-domain proteins was successful. Moreover, competition assays revealed that the new binders could block the natural ligand Neuregulin from binding to ErbB3, indicating a potential anti-proliferative effect. These new binders thus represent promising candidates for further development into ErbB3-signaling inhibitors, where the albumin interaction could result in prolonged in vivo half-life.
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| 27. |
|
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| 28. |
- Nilvebrant, Johan, et al.
(författare)
-
Engineering of Bispecific Affinity Proteins with High Affinity for ERBB2 and Adaptable Binding to Albumin
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e103094-
-
Tidskriftsartikel (refereegranskat)abstract
- The epidermal growth factor receptor 2, ERBB2, is a well-validated target for cancer diagnostics and therapy. Recent studies suggest that the over-expression of this receptor in various cancers might also be exploited for antibody-based payload delivery, e. g. antibody drug conjugates. In such strategies, the full-length antibody format is probably not required for therapeutic effect and smaller tumor-specific affinity proteins might be an alternative. However, small proteins and peptides generally suffer from fast excretion through the kidneys, and thereby require frequent administration in order to maintain a therapeutic concentration. In an attempt aimed at combining ERBB2-targeting with antibody-like pharmacokinetic properties in a small protein format, we have engineered bispecific ERBB2-binding proteins that are based on a small albumin-binding domain. Phage display selection against ERBB2 was used for identification of a lead candidate, followed by affinity maturation using second-generation libraries. Cell surface display and flow-cytometric sorting allowed stringent selection of top candidates from pools pre-enriched by phage display. Several affinity-matured molecules were shown to bind human ERBB2 with sub-nanomolar affinity while retaining the interaction with human serum albumin. Moreover, parallel selections against ERBB2 in the presence of human serum albumin identified several amino acid substitutions that dramatically modulate the albumin affinity, which could provide a convenient means to control the pharmacokinetics. The new affinity proteins competed for ERBB2-binding with the monoclonal antibody trastuzumab and recognized the native receptor on a human cancer cell line. Hence, high affinity tumor targeting and tunable albumin binding were combined in one small adaptable protein.
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| 29. |
- Nilvebrant, Johan, et al.
(författare)
-
Engineering of bispecific affinity proteins with nanomolar affinity for both ErbB2 and albumin
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The epidermal growth factor receptor 2, ErbB2, is a well-validated target for cancer therapy. Recent studies suggest that the over-expression of this receptor in various cancers might also be exploited for antibody-based payload delivery, e.g. antibody drug conjugates. In such strategies, the full-length antibody format is probably not required for therapeutic effect and smaller tumor-antigen specific affinity proteins might be an alternative. However, small proteins and peptides generally suffer from fast excretion through the kidneys, requiring frequent administration in order to maintain a therapeutic concentration. In an attempt aimed at combining ErbB2- targeting with antibody-like pharmacokinetic properties, we have engineered bispecific ErbB2-binding affinity proteins that are based on a small albumin-binding domain. Phage display technology was used for identification of a lead candidate as well as for affinity maturation using second-generation libraries. Affinity matured binders were shown to bind human ErbB2 with high affinity while still retaining the natural interaction with human serum albumin. Hence, two important properties that may be utilized for tumor targeting and in vivo half-life extension were combined in one molecule.
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| 30. |
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| 31. |
- von Witting, Emma, et al.
(författare)
-
ADAPT as a single-domain bispecific scaffold capable of albumin-associated haf-life extension for therapeutic applications
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Albumin-binding fusion partners are frequently used as a means for the in vivo half-life extension of small therapeutic molecules that would normally be cleared very rapidly from circulation. However, in applications where small size is key, fusion to an additional molecule can be disadvantageous. ABD-Derived Affinity ProTeins (ADAPTs) are a type of scaffold proteins based on one of the albumin binding domains of streptococcal Protein G, with newly introduced binding specificities against numerous targets. Here we engineered this scaffold further and showed that this domain, as small as 6 kDa, can harbor two distinct binding surfaces and utilize them to interact with two targets simultaneously. These novel ADAPTs were developed to bind to both serum albumin as well as another clinically relevant target, thus circumventing the need for an albumin binding fusion partner. To accomplish this, we designed a novel phage display library and used it to successfully select for single-domain bispecific binders towards a panel of targets: TNFa, PSA (Prostate Specific Antigen), CRP (C-reactive protein), renin, angiogenin and insulin. Apart from successfully identifying bispecific binders for all targets, we also demonstrated the formation of the ternary complex of the ADAPT together with albumin and each of the four targets TNFa, PSA, angiogenin and insulin. This simultaneous binding of albumin and other targets presents an opportunity to combine the advantages of small molecules with those of larger ones allowing for lower cost of goods and non-invasive administration routes while still maintaining a sufficient in vivo half-life.
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| 32. |
- von Witting, Emma, et al.
(författare)
-
Small Bispecific Affinity Proteins for Simultaneous Target Binding and Albumin-Associated Half-Life Extension
- 2021
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 18:1, s. 328-337
-
Tidskriftsartikel (refereegranskat)abstract
- Albumin-binding fusion partners are frequently used as a means for the in vivo half-life extension of small therapeutic molecules that would normally be cleared very rapidly from circulation. However, in applications where small size is key, fusion to an additional molecule can be disadvantageous. Albumin-derived affinity proteins (ADAPTs) are a new type of scaffold proteins based on one of the albumin-binding domains of streptococcal protein G, with engineered binding specificities against numerous targets. Here, we engineered this scaffold further and showed that this domain, as small as 6 kDa, can harbor two distinct binding surfaces and utilize them to interact with two targets simultaneously. These novel ADAPTs were developed to possess affinity toward both serum albumin as well as another clinically relevant target, thus circumventing the need for an albumin-binding fusion partner. To accomplish this, we designed a phage display library and used it to successfully select for single-domain bispecific binders toward a panel of targets: TNFα, prostate-specific antigen (PSA), C-reactive protein (CRP), renin, angiogenin, myeloid-derived growth factor (MYDGF), and insulin. Apart from successfully identifying bispecific binders for all targets, we also demonstrated the formation of the ternary complex consisting of the ADAPT together with albumin and each of the five targets, TNFα, PSA, angiogenin, MYDGF, and insulin. This simultaneous binding of albumin and other targets presents an opportunity to combine the advantages of small molecules with those of larger ones allowing for lower cost of goods and noninvasive administration routes while still maintaining a sufficient in vivo half-life.
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| 33. |
- Wong, Wan Man, et al.
(författare)
-
Expression of Integrin alpha 2 Receptor in Human Cord Blood CD34+CD38-CD90+Stem Cells Engrafting Long-Term in NOD/SCID-IL2R gamma(c)null Mice
- 2013
-
Ingår i: Stem Cells. - : AlphaMed Press. - 1066-5099 .- 1549-4918. ; 31:2, s. 360-371
-
Tidskriftsartikel (refereegranskat)abstract
- Human hematopoietic stem cells reside in the CD34+CD38-CD90+ population in cord blood and bone marrow. However, this cell fraction is heterogeneous, and the phenotype of the rare primitive stem cells remains poorly defined. We here report that primitive cord blood CD34+CD38-CD90+ stem cells, with the ability to reconstitute NOD/SCID-IL2R gamma(c)null (NSG) mice long-term, at 24 weeks after transplantation, can be prospectively isolated at an increased purity by using integrin alpha 2 receptor as an additional stem cell marker. Using a limiting dilution transplantation assay, we found a highly significant enrichment of multilineage reconstituting stem cells in the CD34+CD38-CD90+ cell fraction expressing the integrin alpha 2 receptor, with a frequency of 1/29 cells, as compared to a frequency of 1/157 in the corresponding integrin alpha 2- cells. In line with this, long-term reconstituting stem cells within the cord blood CD34+CD38- cell population were significantly enriched in the integrin alpha 2+ fraction, while stem cells and progenitors reconstituting short-term, at 8-12 weeks, were heterogeneous in integrin alpha 2 expression. Global gene expression profiling revealed that the lineage-marker negative (Lin-) CD34+CD38-CD90+CD45RA- integrin alpha 2+ cell population was molecularly distinct from the integrin alpha 2- cell population and the more mature Lin-CD34+CD38-CD90-CD45RA- cell population. Our findings identify integrin alpha 2 as a novel stem cell marker, which improves prospective isolation of the primitive human hematopoietic stem cells within the CD34+CD38-CD90+ cell population for experimental and therapeutic stem cell applications. STEM CELLS 2013;31:360-371
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| 34. |
- Åstrand, Annika, 1959-
(författare)
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När PBS kom till byn : Berättelser om erfarenheter av ProblemBaserad Skolutveckling
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis presents a study on different school actors’ narratives about how they have experienced a participation in a school development collaboration called PBS, problem based school development. A school development and research project based at Karlstad University. The analysis is inspired by a narrative approach and a critical perspective on policy, were policy is understood as both text and discourse. The aim of the study is to show how the carrying through of this new policy (PBS) is received and reconstructed in three Swedish municipal settings. In the analysis the participant’s narratives are also related to the reconstructions of the field of education politics that has been carried out the last decades, here in Sweden as well as in other countries around the world. In this study 46 interviews were carried out. Official texts from each of the three school organizations have also been studied. As analytical tools parts of a model called the zoom-model and three different concepts, taken from the field of organization studies have been used. The overall result shows that those who work in schools today are engaged in a large amount of development works, claims and ways of working that they themselves choose to enact. The results also show how the interviewees receive and charge these ideas with their own previous experiences and how this is done in discursive contexts that shape what is considered normal and evident. One conclusion is that further attention ought to be made to the significance of the local context when it comes to carry through a new idea on development and change. A conclusion drawn from how interpretations and reconstructions of both development models prior to PBS and of the national steering model came to play important roles in how PBS was received and reconstructed in the studied municipalities. But different interpretations of the PBS model also led to tensions within and between the different areas of the organizations. Tensions that can be described as dilemmas, implicated by an ongoing cacophony of policy voices, whose prescriptions pull on different directions. When the PBS-policy arrives in this discursive room the results show how this policy can become a tool in line with new discursive narratives of education, regardless the intensions formulated in the context of policy text construction.
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| 35. |
- Åstrand, Max, et al.
(författare)
-
A Neighborhood Selection Strategy for Production Scheduling using CP and LNS
- 2020
-
Ingår i: IEEE International Conference on Emerging Technologies and Factory Automation, ETFA. - : Institute of Electrical and Electronics Engineers Inc.. ; , s. 1183-1186
-
Konferensbidrag (refereegranskat)abstract
- High-quality production scheduling is increasingly important in modern industry operations. We study a class of scheduling problems where jobs take place at predefined locations, as is common in mining, forestry and logistics. The proposed neighborhood selection algorithm is able to find high- quality solutions fast and guarantees that a globally optimal solution is eventually found. Preliminary results are promising.
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| 36. |
- Åstrand, Mikael, 1986-
(författare)
-
Engineering strategies for ABD-derived affinity proteins for therapeutic and diagnostic applications
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small stable protein domains are attractive scaffolds for engineering affinity proteins due to their high tolerance to mutagenesis without loosing structural integrity. The albuminbinding domain is a 5 kDa three-helix bundle derived from the bacterial receptor Protein G with low-nanomolar affinity to albumin. In this thesis, the albumin-binding domain is explored as a scaffold for engineering novel affinity proteins with the possible benefit of combining a prolonged serum half-life with specific targeting in a single small scaffold protein. Previously, a library was created by randomizing surface-exposed residues in order to engineer affinity to a new target antigen in addition to the inherent albumin affinity. Here, phage display selections were separately performed against the tumor antigens ERBB2 and ERBB3. The ERBB3 selection resulted in a panel of candidates that were found to have varying affinities to ERBB3 in the nanomolar range, while still retaining a high affinity to albumin. Further characterization concluded that the clones also competed for binding to ERBB3 with the natural activating ligand Heregulin. The selections against ERBB2 resulted in sub-nanomolar affinities to ERBB2 where the binding site was found to overlap with the antibody Trastuzumab. The binding sites on ABD to albumin and either target were found in both selections to be mutually exclusive, as increased concentrations of albumin reduced the level of binding to ERBB2 or ERBB3. An affinity-matured ERBB2 binder, denoted ADAPT6, which lacked affinity to albumin was evaluated as a radionuclide-labeled imaging tracer for diagnosing ERBB2-positive tumors. Biodistribution studies in mice showed a high renal uptake consistent with affinity proteins in the same size range and the injected ADAPT quickly localized to the implanted tumor. High contrast images could be generated and ERBB2-expressing tissue could be distinguished from normal tissue with high contrast, demonstrating the feasibility of the scaffold for use as diagnostic tool. In a fourth study, affinity maturation strategies using staphylococcal cell-surface display were evaluated by comparing two replicate selections and varying the stringency. A sub-nanomolar target concentration was concluded to be inappropriate for equilibrium selection as the resulting output was highly variable between replicates. In contrast, equilibrium sorting at higher concentrations followed by kinetic-focused off-rate selection resulted in high output overlap between attempts and a clear correlation between affinity and enrichment.
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| 37. |
- Åstrand, Max, et al.
(författare)
-
Fleet scheduling in underground mines using constraint programming
- 2018
-
Ingår i: 15th International Conference on Integration of Constraint Programming, Artificial Intelligence, and Operations Research, CPAIOR 2018. - Cham : Springer. - 9783319930305 ; , s. 605-613
-
Konferensbidrag (refereegranskat)abstract
- The profitability of an underground mine is greatly affected by the scheduling of the mobile production fleet. Today, most mine operations are scheduled manually, which is a tedious and error-prone activity. In this contribution, we present and formalize the underground mine scheduling problem, and propose a CP-based model for solving it. The model is evaluated on instances generated from real data. The results are promising and show a potential for further extensions.
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| 38. |
- Åstrand, Mikael, et al.
(författare)
-
Investigating affinity-maturation strategies and reproducibility of fluorescence-activated cell sorting using a recombinant ADAPT library displayed on staphylococci
- 2016
-
Ingår i: Protein Engineering Design & Selection. - : Oxford University Press. - 1741-0126 .- 1741-0134. ; 29:5, s. 187-195
-
Tidskriftsartikel (refereegranskat)abstract
- During the past decades, advances in protein engineering have resulted in the development of various in vitro selection techniques (e.g. phage display) to facilitate discovery of new and improved proteins. The methods are based on linkage between genotype and phenotype and are often performed in successive rounds of selection. Since the resulting output depends on the selection pressures used and the applied strategy, parameters in each round must be carefully considered. In addition, studies have reported biases that can cause enrichment of unwanted clones and/or low correlation between abundance in output and affinity. We have recently developed a selection method based on display of protein libraries on Staphylococcus carnosus and isolation of affinity proteins by fluorescence-activated cell sorting. Here, we compared duplicate selections for affinity maturation using equilibrium binding at different target concentrations and kinetic off-rate selection. The results showed that kinetic selection is efficient for isolation of high-affinity binders and that equilibrium selection at subnanomolar concentrations should be avoided. Furthermore, the reproducibility of the selection was high and a clear correlation was observed between enrichment and affinity. This work reports on the reproducibility of bacterial display in combination with FACS and provides insights into selection design to help guide the development of new affinity proteins.
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| 39. |
- Åstrand, Max, et al.
(författare)
-
Short-Term Scheduling of Production Fleets in Underground Mines Using CP-Based LNS
- 2021
-
Ingår i: Lecture Notes in Computer Science. - Cham : Springer Nature. ; , s. 365-382
-
Konferensbidrag (refereegranskat)abstract
- Coordinating the mobile production fleet in underground mines becomes increasingly important as the machines are more and more automated. We present a scheduling approach that applies to several of the most important production methods used in underground mines. Our algorithm combines constraint programming with a large neighborhood search strategy that dynamically adjusts the neighborhood size. The resulting algorithm is complete and able to rapidly improve constructed schedules in practice. In addition, it has important benefits when it comes to the acceptance of the approach in real-life operations. Our approach is evaluated on public and private industrial problem instances representing different mines and production methods. We find significant improvements over the current industrial practice.
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| 40. |
- Åstrand, Max
(författare)
-
Short-term Underground Mine Scheduling : Constraint Programming in an Industrial Application
- 2018
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The operational performance of an underground mine depends critically on how the production is scheduled. Increasingly advanced methods are used to create optimized long-term plans, and simultaneously the actual excavation is getting more and more automated. Therefore, the mapping of long-term goals into tasks by manual short-term scheduling is becoming a limiting segment in the optimization chain. In this thesis we study automating the short-term mine scheduling process, and thus contribute to an important missing piece in the pursuit of autonomous mining.First, we clarify the fleet scheduling problem and the surrounding context. Based on this knowledge, we propose a flow shop that models the mine scheduling problem. A flow shop is a general abstract process formulation that captures the key properties of a scheduling problem without going into specific details. We argue that several popular mining methods can be modeled as a rich variant of a k-stage hybrid flow shop, where the flow shop includes a mix of interruptible and uninterruptible tasks, after-lags, machine unavailabilities, and sharing of machines between stages.Then, we propose a Constraint Programming approach to schedule the underground production fleet. We formalize the problem and present a model that can be used to solve it. The model is implemented and evaluated on instances representative of medium-sized underground mines.After that, we introduce travel times of the mobile machines to the scheduling problem. This acknowledges that underground road networks can span several hundreds of kilometers. With this addition, the initially proposed Constraint Programming model struggles with scaling to larger instances. Therefore, we introduce a second model. The second model does not solve the interruptible scheduling problem directly; instead, it solves a related uninterruptible problem and transforms the solution back to the original time domain. This model is significantly faster, and can solve instances representative of large-sized mines even when including travel times.Lastly, we focus on finding high-quality schedules by introducing Large Neighborhood Search. To do this, we present a domain-specific neighborhood definition based on relaxing variables corresponding to certain work areas. Variants of this neighborhood are evaluated in Large Neighborhood Search and compared to using only restarts. All methods and models in this thesis are evaluated on instances generated from an operational underground mine.
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| 41. |
- Åstrand, Max
(författare)
-
Short-term Underground Mine Scheduling : An Industrial Application of Constraint Programming
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The mining industry is facing a surge in automation in the pursuit of safe and profitable operations. As the excavation process is increasingly automated, today's mining companies seek to optimize the coordination of the now automated mining activities. This coordination is called short-term mine scheduling, and it is the process of allocating resources and determining feasible start and end times for the upcoming mining activities. Unfortunately, current industrial practice relies heavily on manual labor, making the performance critically dependent on the expertise of the individual scheduler. In this thesis, we study how to automate the short-term mine scheduling process to increase the efficiency in a vital part of the underground mine planning chain. First, the short-term underground mine scheduling problem is detailed, and the surrounding operational context is clarified. Central aspects of the excavation process are shown to be adequately described by a scheduling abstraction known as a hybrid flow shop. We demonstrate that some popular mine production methods can be considered rich variants of a k-stage hybrid flow shop exhibiting a mix of interruptible and uninterruptible activities, sequence-dependent setup times, and sharing of machines between stages. An approach based on constraint programming is then presented that can be used for short-term scheduling in underground mines. For mines that have vast underground road networks, it is important to consider the travel times needed for the mobile machines between subsequent activities. The proposed extension of the first approach can unfortunately only solve small instances in reasonable computation times. To solve industrially relevant problem sizes, we introduce a second approach. The second approach does not solve the interruptible scheduling problem directly; instead, it solves a related uninterruptible problem and transforms the solution back to the original time domain. It is significantly faster than the first approach and can be used to solve larger instances, even when including travel times. The second approach is also extended to support more general mining scenarios that cannot be described as hybrid flow shops.To improve the quality of the schedules, we introduce a domain-specific neighborhood definition that is used in large neighborhood search. Initially, different fixed neighborhood sizes are investigated. Upon observing that there is no clear dominant strategy, we propose an algorithm for dynamically adjusting the size of the explored neighborhoods. The constructed schedules are improved rapidly using the proposed algorithm, which also introduces local optimality properties that are beneficial when it comes to industrial acceptance. For all models and methods presented in this thesis, we perform extensive numerical evaluations on problem instances derived from operational underground mines.This thesis is concluded by presenting practical experiences from automating the short-term scheduling process in underground mines. Assumptions and design choices are motivated by earlier experiences from using simpler scheduling algorithms. Finally, senior mine schedulers from two different mine sites assess the real-life applicability of the final scheduling approach.
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| 42. |
- Åstrand, Mikael, et al.
(författare)
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Surrogate models for design and study of underground mine ventilation
- 2017
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Konferensbidrag (refereegranskat)abstract
- Ventilation is vital for the production in an underground mine. Therefore, it is important to have efficient and accurate design tools in order to ensure and optimize the airflows in the mine. There are several commercial software for airflow simulation based on first principles. However, the computational cost of simulation together with integrational obstacles when connecting simulation to control strategies limits the benefit of these tools. In this paper an approach utilizing surrogate models as a complementary design tool is presented. It is shown that using surrogate models one can with rather low computational expense evaluate and benchmark different control strategies. It is also shown that the models can be used for identifying possible bottlenecks in the system in advance. Moreover, the use of surrogate models transfer the simulation into a development-friendly environment (such as Matlab). A test case is used based on a real underground mine ventilation design. Two types of surrogate models are fitted to process data; multiple least squares regression and a Gaussian process model. Sensitivity analysis on the surrogate shows the potential of using surrogate models for identifying bottlenecks. Furthermore, the surrogate is used to benchmark two different control strategies for mine ventilation.
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| 43. |
- Åstrand, Max, et al.
(författare)
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Underground mine scheduling modelled as a flow shop : a review of relevant work and future challenges
- 2018
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Ingår i: Journal of the Southern African Institute of Mining and Metallurgy. - Marshalltown, Soth Africa : South African Institute of Mining and Metallurgy. - 2225-6253 .- 2411-9717. ; 118:12, s. 1265-1276
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Tidskriftsartikel (refereegranskat)abstract
- Advanced planning and automation are increasingly important in modern mines. Sophisticated methods for long-term mine planning are often used, and the advent of autonomous machines makes the actual operation more predictable. However, the interface between these two timescales, i.e. the scheduling of the mobile production fleet, often limits the ability to operate mines at maximum profitability. We show how scheduling the production fleet in an underground mine can be modelled as a flow shop. A flow shop is a general abstract process formulation that captures the key properties of a scheduling problem without going into specific details. Thus, the flow shop enables mine scheduling to reap the benefits of scheduling research from other industries. We review recent results from the mining community and the flow shop community, and introduce scheduling methods used in these two fields. This work aims at providing value to researchers from the mining community who want to leverage their skill set, as well as to theoretical researchers by presenting the mining process as a potential application area. Lastly, we discuss the results, and outline some future challenges and opportunities facing the industry.
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| 44. |
- Åstrand, Max, et al.
(författare)
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Underground mine scheduling of mobile machines using Constraint Programming and Large Neighborhood Search
- 2020
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Ingår i: Computers & Operations Research. - : Elsevier BV. - 0305-0548 .- 1873-765X. ; 123
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Tidskriftsartikel (refereegranskat)abstract
- Manual short-term scheduling in underground mines is a time-consuming and error-prone activity. In this work, we present a Constraint Programming approach capable of automating the short-term scheduling process in a cut-and-fill mine. The approach extends previous work by accounting for fleet travel times, and thus captures an important aspect of the real-world machine scheduling problem. We introduce two models: one that directly solves the original interruptible scheduling problem, and one that is based on solving a related uninterruptible scheduling problem and transforming its solution back to the original domain. Large Neighborhood Search is also employed with a domain-specific neighborhood definition that helps to find high-quality schedules faster. Problem instances derived from an operational mine are used to demonstrate the efficacy of our approach.
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