| 1. |
- Aits, Sonja, et al.
(författare)
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HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:5, s. 1008-1019
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Tidskriftsartikel (refereegranskat)abstract
- HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.
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| 2. |
- Brest, Patrick, et al.
(författare)
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Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.
- 2007
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Ingår i: Cancer Research. - 1538-7445. ; 67:23, s. 11327-11334
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Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.
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| 3. |
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| 4. |
- Fischer, Hans, et al.
(författare)
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Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4.
- 2007
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Ingår i: Cellular Microbiology. - : Hindawi Limited. - 1462-5814 .- 1462-5822. ; 9:5, s. 1239-1251
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal Toll-like receptors (TLRs) respond to pathogens, but remain inert to the indigenous flora, suggesting that the TLRs can receive pathogen-specific signals. For example, TLR4 signalling is activated in CD14-negative epithelial cells by P-fimbriated, uropathogenic Escherichia coli, but not by lipopolysaccharide. The fimbriae use glycosphingolipids as recognition receptors and there is release of ceramide, which is the membrane-anchoring domain of the receptors. In this study, ceramide was identified as a TLR4 agonist and as a putative signalling intermediate between the glycosphingolipid recognition receptors and TLR4. Exogenous ceramide activated a TLR4-dependent epithelial cell response, as shown by exposing stably transfected TLR4-positive or -negative human embryonal kidney cells to C2 and C6 ceramide. A similar, TLR4-dependent response occurred after deliberate release of endogenous long-chained ceramide with sphingomyelinase. Microbial ligands with glycosphingolipid specificity (P fimbriae or the B subunit of Shiga toxin) were shown to increase the levels of ceramide and to trigger a TLR4-dependent response in epithelial cells. The results show that ceramide activates TLR4 signalling and suggest that this mechanism might allow pathogens to elicit mucosal TLR4 responses by perturbing sphingolipid receptors for virulence ligands like P fimbriae.
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| 5. |
- Ahmadi, Zainab, et al.
(författare)
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Smoking and home oxygen therapy : a review and consensus statement from a multidisciplinary Swedish taskforce
- 2024
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Ingår i: European Respiratory Review. - : European Respiratory Society. - 0905-9180 .- 1600-0617. ; 33:171
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Forskningsöversikt (refereegranskat)abstract
- Background: Home oxygen therapy (HOT) improves survival in patients with hypoxaemic chronic respiratory disease. Most patients evaluated for HOT are former or active smokers. Oxygen accelerates combustion and smoking may increase the risk of burn injuries and fire hazards; therefore, it is considered a contraindication for HOT in many countries. However, there is variability in the practices and policies regarding this matter. This multidisciplinary Swedish taskforce aimed to review the potential benefits and risks of smoking in relation to HOT, including medical, practical, legal and ethical considerations.Methods: The taskforce of the Swedish Respiratory Society comprises 15 members across respiratory medicine, nursing, medical law and ethics. HOT effectiveness and adverse risks related to smoking, as well as practical, legal and ethical considerations, were reviewed, resulting in five general questions and four PICO (population–intervention–comparator–outcome) questions. The strength of each recommendation was rated according to the GRADE (grading of recommendation assessment, development and evaluation) methodology.Results: General questions about the practical, legal and ethical aspects of HOT were discussed and summarised in the document. The PICO questions resulted in recommendations about assessment, management and follow-up of smoking when considering HOT, if HOT should be offered to people that meet the eligibility criteria but who continue to smoke, if a specific length of time of smoking cessation should be considered before assessing eligibility for HOT, and identification of areas for further research.Conclusions: Multiple factors need to be considered in the benefit/risk evaluation of HOT in active smokers. A systematic approach is suggested to guide healthcare professionals in evaluating HOT in relation to smoking.
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| 6. |
- Andersson, Eva-Lotta, 1966-
(författare)
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Kön och ansvar i sjukförsäkringen : En studie av utredningstexter 1944 - 2006
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent decades, the welfare state has changed as a result of various market adaptations and privatisations. The state’s responsibility for the provision of welfare has diminished and responsibility has been shifted onto the market, the family and civil society.The aim of this thesis is to examine how shifting the responsibility for sickness insurance between the state, the market and the family interacts with ideas and beliefs about gender, and what the consequences are for the eligibility to receive sickness benefit insurance of those who are insured. The material consists of governmental inquiries into the Swedish sickness insurance system from 1944 to 2006, the texts of which have been analysed using discourse analysis.The study shows that the division of responsibility studied in the texts, in various ways, worked to create a hierarchy and to maintain the separation between different categories, and thus has contributed to create gender-defined positions. The design of the sickness insurance system is shaped by gender-defined interpretative frameworks.In the texts I study how divisions of responsibility is characterised by ideas and beliefs about gender. The first period is dominated by an interpretive framework in which the man is the provider and the woman is provided for. These ideas and beliefs about gender characterise the division of responsibility, and those who are insured are separated into gender-defined groups by the way in which responsibility for different parts of the insurance system are divided between the state, the market and the family. As a result, gender-defined status positions are created, with men as policy holders and women as beneficiaries.The second period is dominated by an interpretive framework based on equality of treatment. It is characterised by ideas that both men and women contribute to supporting the household through paid work. Differentiation between the sexes decreases as women, to a much greater extent, positioned as wage-earners, while those who work in the home become increasingly marginalised as they are perceived as old-fashioned.In the third period, economic interpretive frameworks and concepts relating to insurability come, increasingly, to the fore. Differentiation increases as the responsibility is shifted to the market and the individual. The roles of beneficiary and the policy holder return, although the division is not as clearly defined by gender as it was in the first period.
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| 7. |
- Annerback, Eva-Maria, et al.
(författare)
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Child physical abuse and concurrence of other types of child abuse in Sweden : Associations with health and risk behaviors
- 2012
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Ingår i: International Journal of Child Abuse & Neglect. - : Elsevier BV. - 0145-2134 .- 1873-7757. ; 36:7-8, s. 585-595
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine the associations between child physical abuse executed by a parent or caretaker and self-rated health problems/risk-taking behaviors among teenagers. Further to evaluate concurrence of other types of abuse and how these alone and in addition to child physical abuse were associated with bad health status and risk-taking behaviors.Methods: A population-based survey was carried out in 2008 among all the pupils in 2 different grades (15 respectively 17 years old) in Sodermanland County, Sweden (n = 7,262). The response rate was 81.8%. The pupils were asked among other things about their exposure to child physical abuse, exposure to parental intimate violence, bullying, and exposure to being forced to engage in sexual acts. Adjusted analyses were conducted to estimate associations between exposure and ill-health/risk-taking behaviors.Results: Child physical abuse was associated with poor health and risk-taking behaviors with adjusted odds ratios (OR) ranging from 1.6 to 6.2. The associations were stronger when the pupils reported repeated abuse with OR ranging from 2.0 to 13.2. Also experiencing parental intimate partner violence, bullying and being forced to engage in sexual acts was associated with poor health and risk-taking behaviors with the same graded relationship to repeated abuse. Finally there was a cumulative effect of multiple abuse in the form of being exposed to child physical abuse plus other types of abuse and the associations increased with the number of concurrent abuse.Conclusions: This study provides strong indications that child abuse is a serious public health problem based on the clear links seen between abuse and poor health and behavioral problems. Consistent with other studies showing a graded relationship between experiences of abuse and poor health/risk-taking behaviors our study shows poorer outcomes for repeated and multiple abuse. Thus, our study calls for improvement of methods of comprehensive assessments, interventions and treatment in all settings where professionals meet young people.
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| 8. |
- Borgquist, Ola, et al.
(författare)
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Micro- and macromechanical effects on the wound bed of negative pressure wound therapy using gauze and foam.
- 2010
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Ingår i: Annals of Plastic Surgery. - 1536-3708. ; 64:6, s. 789-793
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Tidskriftsartikel (refereegranskat)abstract
- Negative pressure wound therapy (NPWT) results in 2 types of tissue deformation, macrodeformation (ie, wound contraction) and microdeformation (ie, the interaction of tissue and dressing on a microscopic level). These effects have been delineated for one type of wound filler, foam, but not for gauze. The mechanical deformation initiates a signaling cascade which ultimately leads to wound healing. The aim of the present study was to examine the effect of gauze and foam on macro- and microdeformation during treatment with negative pressure. An in vivo porcine peripheral wound model was used. NPWT was applied for 72 hours at 0, -75, and -125 mm Hg, using either foam or gauze as wound filler. The mechanical effects of NPWT were examined by measuring the wound surface area reduction and by histologic analysis of the wound bed tissue. Similar degrees of wound contraction (macrodeformation) were seen during NPWT regardless if foam or gauze was used. After negative pressure had been discontinued, the wound stayed contracted. There was no difference in wound contraction between -75 and -125 mm Hg. Biopsies of the wound bed revealed a repeating pattern of wound surface undulations and small tissue blebs ("tissue mushrooms") were pulled into the pores of the foam dressing and the spaces between the threads in the gauze dressing (microdeformation). This pattern was obvious in wounds treated both with foam and gauze, at atmospheric pressure (0 mm Hg) as well as at subatmospheric pressures (-75 and -125 mm Hg). The degrees of micro- and macrodeformation of the wound bed are similar after NPWT regardless if foam or gauze is used as wound filler.
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| 9. |
- Düringer, Caroline, et al.
(författare)
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HAMLET; a novel tool to identify apoptotic pathways in tumor cells.
- 2005
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Ingår i: Application of apoptosis to cancer treatment.. - Berlin/Heidelberg : Springer-Verlag. - 9781402033032 ; , s. 223-245
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Tumor cells often carry mutations in genes that control cell survival, and become resistant to signals that trigger cell death. Yet, some cell death pathways remain intact in tumor cells. If identified, these pathways might be exploited to selectively remove tumor cells. HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex derived from human milk that activates cell death programs in tumor cells but not in healthy differentiated cells. We use HAMLET as a tool to identify apoptosis and apoptosis-like cell death mechanisms in tumor cells and to understand if these mechanisms differ between tumor and healthy cells. HAMLET interacts with the cell surface, translocates into the cytoplasm and accumulates in cell nuclei, where it disrupts the chromatin. Recent in vivo studies have shown that HAMLET maintains the tumoricidal activity in glioblastoma, papilloma and bladder cancer models, with no significant side effects. The results suggest that HAMLET should be explored as a new therapeutic agent with selectivity for the tumor and with little toxicity for adjacent healthy tissue. Such therapies are a much-needed complement to conventional treatments, to reduce the side effects and improve the selectivity.
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| 10. |
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