| 1. |
- Dahlberg, Lena, 1970-, et al.
(författare)
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Ensamhet bland äldre personer i Norden
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Rapporten presenterar översikter av tidigare forskning och analyser av känslan av ensamhet bland äldre personer. Överlag finns det kunskap om ensamhetens konsekvenser för ohälsa, men det behövs ytterligare forskning där starkare slutsatser kan dras om sambandens riktning, och ett tydligare fokus på ensamhet i gruppen äldre personer. En systematisk översikt visar att det finns god kunskap om en del faktorer som ökar risken för ensamhet, men mer forskning behövs om andra potentiella riskfaktorer. Analyserna visar en relativt låg och stabil förekomst av ensamhet bland äldre personer i Norden, samt att ohälsa och olika indikatorer för social exkludering (t.ex. bristande sociala relationer, otillräcklig inkomst, samt otrygghet i närområdet) har samband med ensamhet. Slutligen konstateras att forskningen om nordiska interventioner för att minska ensamhet bland äldre personer är begränsad.
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| 2. |
- Heldin, Johan, et al.
(författare)
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Dynamin inhibitors impair platelet-derived growth factor beta-receptor dimerization and signaling
- 2019
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Ingår i: Experimental Cell Research. - : ELSEVIER INC. - 0014-4827 .- 1090-2422. ; 380:1, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- The role of plasma membrane composition and dynamics in the activation process of receptor tyrosine kinases (RTKs) is still poorly understood. In this study we have investigated how signaling via the RTK, platelet-derived growth factor beta-receptor (PDGFR-beta) is affected by Dynasore or Dyngo-4a, which are commonly used dynamin inhibitors. PDGFR-beta preferentially internalizes via clathrin-coated pits and in this pathway, Dynamin II has a major role in the formation and release of vesicles from the plasma membrane by performing the membrane scission. We have found that dynamin inhibitors impedes the activation of PDGFR-beta by impairing ligand-induced dimerization of the receptor monomers, which leads to a subsequent lack of phosphorylation and activation both of receptors and downstream effectors, such as ERK1/2 and AKT. In contrast, dynamin inhibitors did not affect epidermal growth factor receptor (EGFR) dimerization and phosphorylation. Our findings suggest that there is a link between plasma membrane dynamics and PDGFR-beta activation, and that this link is not shared with the epidermal growth factor receptor.
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| 3. |
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| 4. |
- Skogar, Örjan, et al.
(författare)
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Parkinson’s disease patients’ subjective descriptions of characteristics of chronic pain, sleeping patterns and health-related quality of life
- 2012
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Ingår i: Neuropsychiatric Disease and Treatment. - 1176-6328 .- 1178-2021. ; 8, s. 435-442
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Nonmotor symptoms are common in Parkinson’s disease (PD). Health-related quality of life (HRQoL) is negatively affected by different factors, of which pain and sleep disturbances are important contributors. This study was performed to evaluate and describe subjective experiences of pain, sleeping patterns, and HRQoL in a cohort of PD patients with chronic pain.Methods: A total of 45 participants with established PD for more than 2 years, and PD-related pain for the preceding three months, were recruited from three sites in Sweden. Data regarding time point for onset, duration and degree of pain parameters, body localization of pain, external influences, and treatments were obtained. HRQoL was evaluated with the Short Form-36® Health Survey, and sleeping patterns were registered with the Parkinson’s disease Sleep Scale, both completed along with a questionnaire.Results: In one-third of participants, pain preceded the PD diagnosis. Median pain score measured with a visual analog scale was 6.6 and 5.9 (for females and males, respectively) the week before the study. In almost half of the participants, pain was present during all their waking hours. Significantly more females described their pain as troublesome, while more males described their pain as irritating. Feelings of numbness and creeping sensations at night were strongly associated with the maximal visual analog scale scores. Polypharmacy was common; 89% used medication for anxiety/insomnia, and 18% used antidepressants. Only one-third of patients who reported pain relief with analgesics had these prescribed on their drug lists. Sleep was characterized by frequent awakenings. Urinary urgency and restless legs were frequently reported as troublesome. Patients rated HRQoL as significantly worse in all items compared with a healthy reference population matched for age and sex.Conclusions: Experiences of chronic PD-related pain are complex; there is substantial sleep fragmentation and negative impact on HRQoL.
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| 5. |
- Stenseke, Marie, et al.
(författare)
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Kris i naturen – vår existens har blivit sårbar
- 2019
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Ingår i: Svenska Dagbladet, Stockholm. - 1101-2412.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Fler arter än någonsin i mänsklighetens historia hotas av utrotning och den biologiska mångfalden lokalt har förändrats kraftigt i en stor del av världens ekosystem. Grundläggande förändringar behövs både i samhället och för individer, för att bromsa den negativa trenden, skriver en rad debattörer.
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| 6. |
- Törnhage, Carl-Johan, et al.
(författare)
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Short- and long-term effects of tactile massage on salivary cortisol concentrations in Parkinsons disease : a randomised controlled pilot study
- 2013
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Ingår i: BMC Complementary and Alternative Medicine. - : BioMed Central (BMC). - 1472-6882. ; 13:357
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Parkinson's disease (PD) is a chronic neurodegenerative disorder with limited knowledge about the normal function and effects of non-pharmacological therapies on the hypothalamic-pituitary-adrenal (HPA) axis. The aim of the study was to analyse the basal diurnal and total secretion of salivary cortisol in short- and long-term aspects of tactile massage (TM).METHODS:Design: Prospective, Controlled and Randomised Multicentre Trial.Setting and interventions: Forty-five women and men, aged 50-79 years, were recruited. Twenty-nine of them were blindly randomised to tactile massage (TM) and 16 of them to the control group, rest to music (RTM). Ten interventions were given during 8 weeks followed by a 26 weeks of follow up. Salivary cortisol was collected at 8 am, 1 pm, 8 pm, and 8 am the next day, on five occasions. With the first and eighth interventions, it was collected immediately before and after intervention.Main outcome measures: The primary aim was to assess and compare cortisol concentrations before and immediately after intervention and also during the follow-up period. The secondary aim was to assess the impact of age, gender, body mass index (BMI), duration and severity of PD, effects of interventional time-point of the day, and levodopa doses on cortisol concentration.RESULTS:The median cortisol concentrations for all participants were 16.0, 5.8, 2.8, and 14.0 nmol/L at baseline, later reproduced four times without significant differences. Cortisol concentrations decreased significantly after TM intervention but no change in diurnal salivary cortisol pattern was found. The findings of reduced salivary cortisol concentrations immediately after the interventions are in agreement with previous studies. However, there was no significant difference between the TM and control groups. There were no significant correlations between cortisol concentrations and age, gender, BMI, time-point for intervention, time interval between anti-parkinson pharmacy intake and sampling, levodopa doses, duration, or severity of PD.CONCLUSIONS:Diurnal salivary cortisol rhythm was normal. Salivary cortisol concentrations were significantly reduced after the TM intervention and after RTM, but there were no significant differences between the groups and no sustained long-term effect. No associations were seen between salivary cortisol concentration and clinical and/or pharmacological characteristics.
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| 7. |
- Wåhlén, Erik, et al.
(författare)
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Activated EGFR and PDGFR internalize in separate vesicles and downstream AKT and ERK1/2 signaling are differentially impacted by cholesterol depletion
- 2023
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 665, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- The interplay between membrane subregions and receptor tyrosine kinases (RTK) will influence signaling in both normal and pathological RTK conditions. In this study, epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor β (PDGFR-β) internalizations were investigated by immunofluorescent microscopy following simultaneous treatment with EGF and PDGF-BB. We found that the two receptors utilize separate routes of internalization, which merges in a common perinuclear endosomal compartment after 45 min of stimulation. This is further strengthened when contrasting the recruitment of either EGFR or PDGFR-β to either clathrin or caveolin-1: PDGFR-β dissociates from caveolin-1 upon stimulation, and engages clathrin, whilst an increased recruitment of EGFR, to both clathrin and caveolin-1, was observed upon EGF stimulation. The association between EGFR and caveolin-1 is supported by the observation that EGFR was localized in lipid raft associated fractions, whereas PDGFR-β was not. We also found that disruption of lipid rafts using MβCD led to an increased EGFR dimerization and phosphorylation in response to ligand, as well as a dramatic decrease in AKT- and a smaller but robust decrease in ERK1/2 phosphorylation. This suggest that lipid rafts may be important to effectively connect the EGFR with downstream proteins to facilitate signaling. Our data implies that cholesterol depletion of the plasma membrane affect the signaling of EGFR and PDGFRβ differently.
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| 8. |
- Wåhlén, Erik, et al.
(författare)
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Differential impact of lipid raft depletion on platelet-derived growth factor (PDGF)-induced ERK1/2 MAP-kinase, SRC and AKT signaling
- 2022
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Ingår i: Cellular Signalling. - : Elsevier. - 0898-6568 .- 1873-3913. ; 96
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Tidskriftsartikel (refereegranskat)abstract
- It has become clear that lipid rafts functions as signaling hotspots connecting cell surface receptors to intracellular signaling pathways. However, the exact involvement of lipid rafts in receptor tyrosine kinase signaling is still poorly understood. In this study, we have analyzed platelet-derived growth factor (PDGF) receptor β (PDGFR-β) signaling in two different cell lines depleted of cholesterol, and as a consequence, disruption of lipid rafts. Cholesterol depletion of BJ-hTERT fibroblasts using methyl-β-cyclodextrin (MβCD) did not affect PDGFR-β activation as measured by its tyrosine phosphorylation. However, we did observe a small reduction in AKT phosphorylation and a more robust decrease of ERK1/2 activation. In contrast, in the osteosarcoma cell line U2OS, we noticed a deficient receptor activation. Interestingly, in U2OS cells, the ERK1/2 pathway was unaffected, but instead AKT and SRC signaling was reduced. These results suggest that cell type specific wiring of signaling pathways can lead to differential sensitivity to cholesterol depletion. Furthermore, MβCD treatment had a much more pronounced morphological effect on U2OS compared to BJ-hTERT cells. This is consistent with a previous report claiming that cancer cells are more sensitive to cholesterol depletion than normal cells. Our data supports the possibility that cholesterol lowering drugs may impede tumor growth.
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| 9. |
- Wåhlén, Erik, et al.
(författare)
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Silencing of Rho GTPases Cdc42, Rac1 or RhoA reduces PDGFRα and -β phosphorylation and downstream signaling of STAT1 and STAT3
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Platelet-derived growth factor receptors (PDGFR) have been implicated in both pathological and physiological signaling and play a major role in the homeostasis of the tumor microenvironment. It has previously been shown that Cdc42, which belongs to the family of Rho GTPases, impairs the degradation of EGFR and VEGFR2. In the current work, we have investigated how Cdc42 as well as Rac1 and RhoA affect PDGFRα and -β signaling and downstream activation of AKT, ERK1/2, STAT1 and STAT3. In response to individual depletion of all Rho GTPases both PDGFRα and -β show a significant reduction in their phosphorylation. We could see a delayed internalization in response to Cdc42 or Rac1 depletion and an increased steady-state amount in response to RhoA depletion for both PDGFRα and -β. Downstream of both receptors, we saw a dramatic effect on STAT signaling, however, AKT and ERK1/2 signaling was unaffected. PDGF-BB-induced STAT1 and STAT3 phosphorylation was severely impaired in response to the depletion of either Cdc42, Rac1 or RhoA. Furthermore, STAT1 protein levels were also decreased in response to depletion of the Rho GTPases. In conclusion, we show that both PDGFRα and PDGFRβ rely on Cdc42, Rac1 and RhoA for proper signaling. Furthermore, we also show that STAT1 and STAT3 depend on Cdc42, Rac1 and RhoA for their signaling downstream of PDGFRs, and STAT1 for its protein stability.
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| 10. |
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| 11. |
- Agnarsdóttir, Margrét, et al.
(författare)
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SOX10 expression in superficial spreading and nodular malignant melanomas
- 2010
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Ingår i: Melanoma research. - 0960-8931 .- 1473-5636. ; 20:6, s. 468-478
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Tidskriftsartikel (refereegranskat)abstract
- SOX10 is a transcription factor expressed in nerve cells and melanocytes. The aim of this study was to investigate the protein expression pattern of SOX10 in malignant melanoma tumors and to analyze whether the results correlated with clinical parameters and the proliferation marker Ki-67. Furthermore, proliferation and migration were analyzed in three different cell lines employing SOX10 small interfering RNA-mediated silencing. Expression patterns were determined in 106 primary tumors and 39 metastases in addition to 16 normal skin samples and six benign nevi employing immunohistochemistry and tissue microarrays. The immunohistochemical staining was evaluated manually and with an automated algorithm. SOX10 was strongly expressed in the benign tissues, but for the malignant tumors superficial spreading melanomas stained stronger than nodular malignant melanomas (P = 0.008). The staining intensity was also inversely correlated with T-stage (Spearman's rho = -0.261, P = 0.008). Overall survival and time to recurrence were significantly correlated with SOX10 intensity, but not in multivariate analysis including T-stage. With the automated algorithm there was an inverse correlation between the SOX10 staining intensity and the proliferation marker, Ki-67 (rho = -0.173, P = 0.02) and a significant difference in the intensity signal between the benign tissues, the primary tumors and the metastases where the metastases stained the weakest (P <= 0.001). SOX10 downregulation resulted in variable effects on proliferation and migration rates in the melanoma cell lines. In conclusion, the SOX10 intensity level differed depending on the tissue studied and SOX10 might have a role in survival. No conclusion regarding the role of SOX10 for in-vitro proliferation and migration could be drawn. Melanoma Res 20:468-478
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| 12. |
- Amagasaki, Kenichi, et al.
(författare)
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c-Jun N-terminal kinase is necessary for platelet-derived growth factor-mediated chemotaxis in primary fibroblasts
- 2006
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Ingår i: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology, Inc.. - 0021-9258 .- 1083-351X. ; 281:31, s. 22173-22179
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Tidskriftsartikel (refereegranskat)abstract
- c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family. It has become clear that JNK does not only have a role in induction of stress responses but also in processes such as cell movement. In this report we demonstrate that JNK activity is necessary for platelet-derived growth factor (PDGF)-BB-induced chemotaxis of primary foreskin fibroblasts and in other cell types. PDGF-BB stimulation was found to lead to activation of JNK with a maximum after 30 min. Inhibition of JNK reduced Ser178 phosphorylation of the focal adhesion component paxillin. Paxillin phosphorylation at this site has been shown to be involved in the dynamics of focal adhesions and consequently cell migration. Moreover, we observed localization of JNK to the actin-dense membrane ruffles induced by PDGF-BB stimulation both using immunofluorescence staining and green fluorescent protein-tagged JNK. This suggests a role for JNK at the leading edge of the cell compatible with a function in cell migration. Furthermore, we show that phosphatidylinositol 3-kinase (PI 3-kinase), which has an established role in PDGF-stimulated cell migration, is necessary for PDGF-induced activation of JNK. In conclusion, JNK is a critical component downstream of PI 3-kinase that may be involved in PDGF-stimulated chemotaxis presumably by modulating the integrity of focal adhesions by phosphorylating its components.
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| 13. |
- Arora, Deepika, et al.
(författare)
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Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells : FLT3 ITD sustains high levels of DUSP6 expression
- 2012
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Ingår i: Cell Communication and Signaling. - 1478-811X. ; 10:1, s. 19-
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Tidskriftsartikel (refereegranskat)abstract
- Protein-tyrosine phosphatases (PTPs) are important regulators of cellular signaling and changes in PTP activity can contribute to cell transformation. Little is known about the role of PTPs in Acute Myeloid Leukemia (AML). The aim of this study was therefore to establish a PTP expression profile in AML cells and to explore the possible role of FLT3 ITD (Fms-like tyrosine kinase 3 with internal tandem duplication), an important oncoprotein in AML for PTP gene expression. PTP mRNA expression was analyzed in AML cells from patients and in cell lines using a RT-qPCR platform for detection of transcripts of 92 PTP genes. PTP mRNA expression was also analyzed based on a public microarray data set for AML patients. Highly expressed PTPs in AML belong to all PTP subfamilies. Very abundantly expressed PTP genes include PTPRC, PTPN2, PTPN6, PTPN22, DUSP1, DUSP6, DUSP10, PTP4A1, PTP4A2, PTEN, and ACP1. PTP expression was further correlated with the presence of FLT3 ITD, focusing on a set of highly expressed dual-specificity phosphatases (DUSPs). Elevated expression of DUSP6 in patients harboring FLT3 ITD was detected in this analysis. The mechanism and functional role of FLT3 ITD-mediated upregulation of DUSP6 was then explored using pharmacological inhibitors of FLT3 ITD signal transduction and si/shRNA technology in human and murine cell lines. High DUSP6 expression was causally associated with the presence of FLT3 ITD and dependent on FLT3 ITD kinase activity and ERK signaling. DUSP6 depletion moderately increased ERK1/2 activity but attenuated FLT3 ITD-dependent cell proliferation of 32D cells. In conclusion, DUSP6 may play a contributing role to FLT3 ITD-mediated cell transformation.
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| 14. |
- Brabec, Jan, et al.
(författare)
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Histogram analysis of tensor-valued diffusion MRI in meningiomas : Relation to consistency, histological grade and type
- 2022
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 33
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach.PURPOSE: To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type.MATERIALS AND METHODS: 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm2. The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components-the anisotropic and isotropic kurtoses (MKA and MKI). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor ("whole-tumor") and within brain tissue in the immediate periphery outside the tumor ("rim") by histogram analysis.RESULTS: Lower 10th percentiles of MK and MKA in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MKA 10 and p = 0.04 for MK10) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MKI in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MKI maps we observed elevated rim-like structure that could be associated with grade. Higher median MKA and lower median MKI distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MKA 50 and p = 0.03 and p = 0.04 for MKI 50).CONCLUSION: Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.
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| 15. |
- Celeste, R. K., et al.
(författare)
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Social Mobility and Tooth Loss : A Systematic Review and Meta-analysis
- 2022
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Ingår i: Journal of Dental Research. - : SAGE Publications. - 0022-0345 .- 1544-0591. ; 101:2, s. 143-150
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Forskningsöversikt (refereegranskat)abstract
- This study systematically reviews the evidence of the association between life course social mobility and tooth loss among middle-aged and older people. PubMed, Scopus, Embase, and Web of Science were systematically searched in addition to gray literature and contact with the authors. Data on tooth loss were collated for a 4-category social mobility variable (persistently high, upward or downward mobility, and persistently low) for studies with data on socioeconomic status (SES) before age 12 y and after age 30 y. Several study characteristics were extracted to investigate heterogeneity in a random effect meta-analysis. A total of 1,384 studies were identified and assessed for eligibility by reading titles and abstracts; 21 original articles were included, of which 18 provided sufficient data for a meta-analysis with 40 analytical data sets from 26 countries. In comparison with individuals with persistently high social mobility, the pooled odds ratios (ORs) for the other categories were as follows: upwardly mobile, OR = 1.73 (95% CI, 1.53 to 1.95); downwardly mobile, OR = 2.52 (95% CI, 2.19 to 2.90); and persistently low, OR = 3.96 (95% CI, 3.13 to 5.03). A high degree of heterogeneity was found(I2 > 78%), and subgroup analysis was performed with 17 study-level characteristics; however, none could explain heterogeneity consistently in these 3 social mobility categories. SES in childhood and adulthood is associated with tooth loss, but the high degree of heterogeneity prevented us from forming a robust conclusion on whether upwardly or downwardly mobile SES may be more detrimental. The large variability in effect size among the studies suggests that contextual factors may play an important role in explaining the difference in the effects of low SES in different life stages (PROSPERO CRD42018092427).
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| 16. |
- Celeste, R. K., et al.
(författare)
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Socioeconomic Life Course Models and Oral Health : A Longitudinal Analysis
- 2020
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Ingår i: Journal of Dental Research. - : SAGE Publications. - 0022-0345 .- 1544-0591. ; 99:3, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- We compared socioeconomic life course models to decompose the direct and mediated effects of socioeconomic status (SES) in different periods of life on late-life oral health. We used data from 2 longitudinal Swedish studies: the Level of Living Survey and the Swedish Panel Study of Living Conditions of the Oldest Old. Two birth cohorts (older, 1925 to 1934; younger, 1944 to 1953) were followed between 1968 and 2011 with 6 waves. SES was measured with 4 indicators of SES and modeled as a latent variable. Self-reported oral health was based on a tooth conditions question. Variables in the younger and older cohorts were grouped into 4 periods: childhood, young/mid-adulthood, mid /late adulthood, late adulthood/life. We used structural equation modeling to fit the following into lagged-effects life course models: 1) chain of risk, 2) sensitive period with late-life effect, 3) sensitive period with early- and late-life effects, 4) accumulation of risks with cross-sectional effects, and 5) accumulation of risks. Chain of risk was incorporated into all models and combined with accumulation, with cross-sectional effects yielding the best fit (older cohort: comparative fit index = 0.98, Tucker-Lewis index = 0.98, root mean square error of approximation = 0.04, weighted root mean square residual = 1.51). For the older cohort, the chain of SES from childhood -> mid-adulthood -> late adulthood -> late life showed the following respective standardized coefficients: 053, 0.92, and 0.97. The total effect of childhood SES on late-life tooth loss (standardized coefficient: -0.23 for older cohort, -0.17 for younger cohort) was mediated by previous tooth loss and SES. Cross-sectional effects of SES on tooth loss were observed throughout the life course, but the strongest coefficients were at young/mid-adulthood (standardized coefficient: -0.41 for older cohort, -0.45 for younger cohort). SES affects oral health cumulatively over the life course and through a chain of risks. Actions to improve socioeconomic conditions in early life might have long-lasting effects on health if they help prevent people from becoming trapped in a chain of risks.
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| 17. |
- Chitu, V., et al.
(författare)
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The PDGFR Receptor Family
- 2015
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Ingår i: Receptor Tyrosine Kinases: Family and Subfamilies. - Cham : Springer International Publishing. - 9783319118871 - 9783319118888 ; , s. 373-538
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Bokkapitel (refereegranskat)
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| 18. |
- Classen, Jean-Francois, et al.
(författare)
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Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:4, s. 1137-1144
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc. METHODS: Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center. RESULTS: Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFRalpha or PDGFRbeta in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal. CONCLUSION: The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.
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| 19. |
- Dahlberg, Lena, 1970-, et al.
(författare)
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A social exclusion perspective on loneliness in older adults in the Nordic countries
- 2022
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Ingår i: European Journal of Ageing. - : Springer Science and Business Media LLC. - 1613-9372 .- 1613-9380. ; 19:2, s. 175-188
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Tidskriftsartikel (refereegranskat)abstract
- Several factors associated with loneliness are also considered indicators of social exclusion. While loneliness has been proposed as an outcome of social exclusion, there is limited empirical evidence of a link. This study examines the associations between social exclusion indicators and loneliness in older adults (60+ years) in four Nordic countries. Data from four waves of the European Social Survey were pooled, providing a total of 7755 respondents (Denmark n = 1647; Finland n = 2501, Norway n = 1540; Sweden n = 2067). Measures of loneliness, demographic characteristics, health, and eight indicators of social exclusion were selected from the survey for analysis. Country-specific and total sample hierarchical logistic regression models of loneliness were developed. Significant model improvement occurred for all models after social exclusion indicators were added to models containing only demographic and health variables. Country models explained between 15.1 (Finland) and 21.5% (Sweden) of the variance in loneliness. Lower frequency of social contacts and living alone compared to in a two-person household was associated with a higher probability of loneliness in all countries, while other indicators were associated with loneliness in specific countries: lower neighbourhood safety (Sweden and Denmark); income concern (Sweden and Finland); and no emotional support (Denmark, Finland, and Sweden). A robust relationship was apparent between indicators of social exclusion and loneliness with the direction of associations being highly consistent across countries, even if their strength and statistical significance varied. Social exclusion has considerable potential for understanding and addressing risk factors for loneliness.
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| 20. |
- Dahlberg, Lena, 1970-, et al.
(författare)
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Trends and gender associations in social exclusion in older adults in Sweden over two decades
- 2020
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Ingår i: Archives of gerontology and geriatrics (Print). - : Elsevier BV. - 0167-4943 .- 1872-6976. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- Background: Social exclusion in older adults is associated with lower well-being and poorer health. To date there has been little research on whether the level of social exclusion in older adults changes over time, and its association with gender.Aim: To examine trends and gender associations in social exclusion indicators in older adults for the years 1992, 2002 and 2011.Methods: Three waves of data from the Swedish Panel Study of Living Conditions of the Oldest Old (SWEOLD), a national survey of adults aged 77 years or older, were analysed: 1992 (n = 537), 2002 (n = 621), and 2011 (n = 904). Summative scales were created for four domains of social exclusion: material resources, social relations and leisure activities, civic participation, and services. Associations between gender and social exclusion within waves were examined as were trends in social exclusion across years.Results: The analyses of trends found significant reductions in exclusion in the domains of material resources and services. Higher levels of exclusion from material resources and civic participation were found in women than men. Within domains, significant trends and gender associations in exclusion were found on several indicators, with indicators showing opposing trends.Conclusion: Although levels of social exclusion have reduced in certain domains during the years examined, our results reflect the persistence of social exclusion in the population of older adults. This underlines the continuing importance of a well-developed welfare and social security system to ensure the social inclusion of vulnerable groups such as older adults.
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| 21. |
- Dahlberg, Lena, 1970-, et al.
(författare)
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Trends in social exclusion among older women and men in Sweden
- 2018
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Konferensbidrag (refereegranskat)abstract
- Background: Social exclusion is a framework for understanding the complexity of disadvantage across various domains of life such as material resources, social relations, civic activities and services. Reviews have identified a lack of gender perspective in social exclusion research. This paper will introduce the framework of social exclusion, and examine trends over time in the levels of social exclusion across different life domains for older women and men in Sweden.Methods: Data on indicators of social exclusion were analysed from respondents aged 76+ years who participated in the 1992, 2002 and 2011 waves of the nationally representative Swedish Panel Study of Living Conditions of the Oldest Old (SWEOLD).Results: There was evidence of a gender different in exclusion from material resources and civic activities, from which women were more often excluded than men. Regardless of gender there were improvements in access to material resources, such as owning a house/apartment. Social contacts (visiting or being visited by friends) decreased over time, while engagement in cultural activities and going to restaurants increased.Conclusions: Trends in social exclusion in older adults over the last 20 years are dependent on the domain considered. Over a range of indicators, older women were more vulnerable to exclusion than men, which needs to be taken into account in policy to combat exclusion.
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| 22. |
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| 23. |
- Eger, Glenda, et al.
(författare)
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NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9, s. e109047-
-
Tidskriftsartikel (refereegranskat)abstract
- The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth.
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| 24. |
- Eger, Glenda, 1984-
(författare)
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Regulation and Function of MAP Kinases in PDGF Signaling
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Platelet-derived growth factor (PDGF) is a family of signaling molecules that stimulates cell growth, survival and migration. PDGF is recognized by specific transmembrane proteins, the PDGF receptors, which relay the signals to the cell activating the Mitogen-activated protein (MAP) kinases and other signaling pathways. Aberrant activation of these pathways is frequently detected in cancer. Hence, the study of these processes is essential for identifying potential drug targets or diagnostic markers.In paper I, we identified Receptor Subfamily 4 Group A Member 1 NR4A1 to be regulated by PDGF via MAP kinases, clarifying the role of Extracellular signal–regulated kinases (Erk) 1/2, Erk5 and Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in its regulation. NR4A1 was found to be important for the tumorigenic potential, measured as anchorage-independent growth, of glioblastoma cells.Since the cellular responses elicited by PDGF result from the balance between phosphorylation and dephosphorylation events, we investigated the role of the dual specificity phosphatases DUSP4/MKP-2 and DUSP6/MKP-3. In paper II, we describe the crucial role of Erk1/2 and p53 in the expression of DUSP4/MKP2. Moreover, we observed that DUSP4/MKP-2 downregulation decreases Erk5 activation and accelerates PDGFRβ internalization and downregulation resulting in a specific inhibition of Signal transducers and activators of transcription (Stat) 3, Src and protein kinase C (PKC), and partially of p38, Stat1/5 and Phoshoplipase Cγ (PLCγ).In paper III, we report that DUSP6/MKP-3 creates a negative cross-talk between Erk1/2 and Erk5 and an auto-inhibitory feedback loop on the PI3-kinase/Akt pathway. In paper IV, we identify a new regulative mechanism of the PDGF pathway. PDGF induces Erk5 expression and activation that modulates the PDGFRβ activity. After Erk5 downregulation, the receptor undergoes to a faster and stronger activation that results in a faster internalization and degradation.In conclusion, we present a mechanism through which the PDGF/MAP kinases support tumor growth, and elucidate different regulatory pathways involved in PDGF signaling.
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| 25. |
- Ekerljung, Lina, et al.
(författare)
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Dimeric HER2-specific affibody molecules inhibit proliferation of the SKBR-3 breast cancer cell line
- 2008
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 377:2, s. 489-494
-
Tidskriftsartikel (refereegranskat)abstract
- HER2-specific affibody molecules in different formats have previously been shown to be useful tumor targeting agents for radionuclide-based imaging and therapy applications, but their biological effect on tumor cells is not well known. In this study, two dimeric ((ZHER2:4)2 and (ZHER2:342)2) and one monomeric (ZHER2:342) HER2-specific affibody molecules are investigated with respect to biological activity. Both (ZHER2:4)2 and (ZHER2:342)2 were found to decrease the growth rate of SKBR-3 cells to the same extent as the antibody trastuzumab. When the substances were removed, the cells treated with the dimeric affibody molecules continued to be growth suppressed while the cells treated with trastuzumab immediately resumed normal proliferation. The effects of ZHER2:342 were minor on both proliferation and cell signaling. The dimeric (ZHER2:4)2 and (ZHER2:342)2 both reduced growth of SKBR-3 cells and may prove therapeutically useful either by themselves or as carriers of radionuclides or other cytotoxic agents.
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| 26. |
- Ekerljung, Lina, et al.
(författare)
-
Effects of HER2-binding affibody molecules on intracellular signaling pathways
- 2006
-
Ingår i: Tumor Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 27:4, s. 201-210
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: HER2, which is overexpressed in 25-30% of human breast cancers, is a tyrosine kinase receptor critical for the signal transduction network that regulates proliferation, migration and apoptosis of cells. METHOD: We report the effects of two novel HER2-binding affibody molecules (Affibody), (ZHER2:4)2 and ZHER2:342, on intracellular signal transduction pathways (Erk1/2, Akt and PLCgamma1) using quantitative immunoblotting techniques and their biological effects in cell culture. The clinically approved antibody trastuzumab (Herceptin) was used as reference substance. RESULTS: Our data showed that, although all substances target HER2, the effects on the receptor and signaling molecules differed. For example, HER2 phosphorylation was induced by trastuzumab and (ZHER2:4)2 but inhibited by ZHER2:342. The effects these substances had on signal transduction correlated to some degree with changes in growth and migration, e.g. (ZHER2:4)2 stimulated phosphorylation of Erk1/2 and PLCgamma1, as well as growth and migration, while ZHER2:342 did not. ZHER2:342 even inhibited phosphorylation of PLCgamma1 and migration. CONCLUSION: Our data suggest that ZHER2:342 is a promising small agent (7 kDa) that may be used as an alternative, or complement, to trastuzumab. If radiolabelled, it can hopefully also be used for HER2 imaging and radionuclide therapy.
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| 27. |
- Ekerljung, Lina, 1980-
(författare)
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EGFR- and HER2-Binding Affibody Molecules : Cellular studies of monomeric, dimeric and bispecific ligands
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abnormal expression and signaling of the ErbB receptors is associated with the development and progression of several forms of cancer. In this thesis, new ErbB-targeting affibody molecules are evaluated regarding their cellular effects in vitro. Since ligand binding to an ErbB receptor might have an impact on the cell it is important to be aware of these effects as they may have consequences for the continued growth of the tumor when used in vivo. The affibody molecules are intended for tumor targeting with the prospect of clinical use in imaging or therapy. Three types of affibody molecules were studied, HER2-binding, EGFR-binding and bispecific binders that target both EGFR and HER2. The HER2-targeting (ZHER2:342)2 showed promising characteristics. It sensitized SKBR-3 cells to irradiation and decreased cell growth to the same extent as the clinically approved antibody Herceptin. The monomeric version, ZHER2:342, did not induce any large effects on intracellular signaling or biological outcome. This makes (ZHER2:342)2 interesting for therapy purposes, while ZHER2:342 may be better suited for imaging. The bispecific affibody molecules were all able to simultaneously bind to both EGFR and HER2, but none of the six constructs resulted in any large effects on cellular outcome. Interestingly, all three monovalent binders are more functional when positioned at the N-terminal part of the construct and the (S4G)3 linker renders higher affinity of the bispecific binders compared to (G4S)3. Tumors that co-express several ErbB receptors are often more aggressive and associated with a worse prognosis, suggesting that the total ErbB expression pattern might be more informative than the expression level of one receptor regarding cancer prognosis and prediction of response to targeted therapies. Bispecific ligands could thus be used as imaging agents with prognostic value. Another aspect of dual targeting is the possibility of increased tumor specificity since tumors are more likely than healthy tissue to express high amounts of two receptors.
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| 28. |
- Ekerljung, Lina, 1980-, et al.
(författare)
-
The HER2-binding Affibody Molecule (ZHER2:342)2 Increases Radiosensitivity in SKBR-3 cells
- 2012
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11, s. e49579-
-
Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that the HER2-specific affibody molecule (ZHER2:342)2 inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (ZHER2:342)2 sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (ZHER2:342)2 and 8 Gy (S8Gy 0.006) was decreased by a factor of 4 compared to the untreated (S8Gy 0.023). The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (ZHER2:342)2. Treatment by (ZHER2:342)2 strongly increased the levels of dimerized and phosphorylated HER2 already after 5 minutes of stimulation. The monomeric ZHER2:342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.
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| 29. |
- Ekman, Simon, et al.
(författare)
-
Activation of growth factor receptors in esophageal cancer : implications for therapy
- 2007
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Ingår i: The Oncologist. - : Oxford University Press (OUP). - 1083-7159 .- 1549-490X. ; 12:10, s. 1165-1177
-
Forskningsöversikt (refereegranskat)abstract
- Esophageal cancer is a highly aggressive disease and is the seventh most common cause of cancer-related death in the western world. Worldwide, it ranks as the sixth most frequent cause of cancer death. Despite advances in surgical techniques and treatment, the prognosis of esophageal cancer remains poor, with very few long-term survivors. The need for novel strategies to detect esophageal cancer earlier and to improve current therapy is urgent. It is well established that growth factors and growth factor receptor-mediated signaling pathways are important components of the transformation process in many forms of cancer, including esophageal cancer. With the recent advances in drug development, there are emerging possibilities to use growth factor signal transduction pathways in targeted therapy. This review provides a summary of the role of growth factors and their receptors in esophageal cancer and discusses their potential roles as biomarkers and as targets in therapy.
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| 30. |
- Ekman, Simon, et al.
(författare)
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Esophageal cancer : current and emerging therapy modalities
- 2008
-
Ingår i: Expert Review of Anticancer Therapy. - : Informa UK Limited. - 1473-7140 .- 1744-8328. ; 8:9, s. 1433-1448
-
Forskningsöversikt (refereegranskat)abstract
- During the last few years, there has been a gradual increase in treatment options for patients with esophageal malignancies. Several clinical studies have been performed, covering not only radiation and chemotherapy, but also the introduction of novel biological agents into the treatment arsenal. Patients with esophageal carcinoma are now offered second-line and sometimes even third-line treatments, and the number of research protocols is increasing. Despite the newly awakened interest in this malignancy, the overall 5-year survival rate has remained at approximately 10% since the 1980s. This review contains a compilation of available studies of esophageal malignancies and discusses current treatment options as well as newly developed therapies targeted at growth factor receptors.
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| 31. |
- Ekman, Simon, et al.
(författare)
-
Hsp90 as a therapeutic target in patients with oesophageal carcinoma
- 2010
-
Ingår i: Expert opinion on therapeutic targets. - : Informa Healthcare. - 1472-8222 .- 1744-7631. ; 14:3, s. 317-328
-
Forskningsöversikt (refereegranskat)abstract
- Importance of the field: Oesophageal carcinoma has a poor prognosis with a 5-year overall survival rate of only 10 - 20%. The disease is often diagnosed at a late stage, when dissemination may already have occurred, contributing to the poor prognosis. However, recent developments in targeted therapy now offer new possibilities in the treatment arsenal. Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation, thus promoting cell growth and survival. Hsp90 has been found to be abundantly expressed in oesophageal cancer and may serve as a therapeutic target in the treatment of this disease. Areas covered in this review: We have summarised available data concerning the role of Hsp90 in oesophageal carcinoma as well as available information on other tumour types. What the reader will gain: To be able to elaborate on the molecular mechanisms of action of Hsp90 and discuss state-of-the-art of clinical trials involving Hsp90 inhibitors in malignancies, with a special emphasis on oesophageal cancer. Take home message: Preclinical studies on Hsp90 inhibition in oesophageal cancer are promising and it is anticipated that in the near future clinical trials with Hsp90 inhibitors will be initiated also for oesophageal cancer, using the experience from other trials.
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| 32. |
- Eriksson, Ove, 1956-, et al.
(författare)
-
Concepts for Integrated Research in Historical Ecology
- 2018
-
Ingår i: Issues and Concepts in Historical Ecology: ThePast and Future of Landscapes and regions. - Cambridge : Cambridge University Press. - 9781108420983 - 9781108355780 ; , s. 145-181
-
Bokkapitel (refereegranskat)
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| 33. |
- Eyjólfsdóttir, Harpa Sif, et al.
(författare)
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Are trajectories of self-rated health and physical working capacity during the retirement transition predicted by work-related factors and social class?
- 2024
-
Ingår i: Work, Aging and Retirement. - 2054-4642 .- 2054-4650.
-
Tidskriftsartikel (refereegranskat)abstract
- We aimed to identify short and long-term trajectories of self-rated health (SRH) and physical working capacity during the retirement transition, and investigate whether work-related factors and social class predict belonging to these trajectories. We used the representative, biennial Swedish Longitudinal Occupational Survey of Health (SLOSH) 2006–2018. We applied group-based trajectory modeling with B-spline smoothers to model trajectories of SRH (n = 2,183) and physical working capacity (n = 2,152) during the retirement transition. Multinomial logistic regression analyses were conducted to investigate trajectory belonging by work-related factors and social class. There was a small “honeymoon effect” in SRH for the total sample. We found four trajectories of SRH and five of physical working capacity. The large majority sustained excellent or good SRH and physical working capacity throughout the study period. Almost 6% had Fairly poor SRH and physical working capacity starting from years before retirement, which remained throughout the study period. High job demands, low job control, adverse physical working conditions, and being in manual occupation increased the likelihood of belonging to the trajectory groups Deteriorating or Fairly poor when compared with the Excellent trajectory group for both SRH and physical working capacity. Our findings suggest that for most people health status is already established some years’ preretirement and maintained for years after retirement, except a short improvement in SRH in accordance with a honeymoon effect. In order to improve health and employability, interventions focusing on working environment should be aimed at younger and midlife employees as well as older workers.
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| 34. |
- Eyjólfsdóttir, Harpa S., et al.
(författare)
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Physical functioning as a predictor of retirement : Has its importance changed over a thirty-year period in Sweden?
- 2022
-
Ingår i: European Journal of Ageing. - : Springer Science and Business Media LLC. - 1613-9372 .- 1613-9380. ; 19:4, s. 1417-1428
-
Tidskriftsartikel (refereegranskat)abstract
- Many countries, including Sweden, are implementing policies aimed at delaying retirement and encouraging older workers to remain on the labour market for longer. During recent decades, there have been several major reforms to the pension and social security systems in Sweden. Moreover, the nature of occupations has shifted towards more non-manual and sedentary activities, older women are today almost as active in the labour market as men in Sweden, and physical functioning has improved over time. In this study, we investigate whether the importance of physical functioning as a predictor for retirement has changed over time, for women and men, respectively. We used four waves of nationally representative data from The Swedish Level of Living Survey from 1981, 1991, 2000, and 2010, together with income register data. We found that greater severity of musculoskeletal pain and mobility limitations increased the likelihood of retirement in all waves. Results from logistic regression models with average marginal effects and predictive margins showed that there is a trend towards physical functioning becoming less important for retirement towards the end of the study period, especially for women, when controlling for occupational-based social class, age, adverse physical working conditions, and job demands. People, especially women, reporting impaired physical functioning did not retire to the same extent as in previous decades. This indicates that people stayed longer in the labour market despite impaired physical functioning, which may have repercussions on well-being and quality of life.
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| 35. |
- Eyjólfsdóttir, Harpa S., et al.
(författare)
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Prolongation of working life and its effect on mortality and health in older adults : Propensity score matching
- 2019
-
Ingår i: Social Science and Medicine. - : Elsevier BV. - 0277-9536 .- 1873-5347. ; 226, s. 77-86
-
Tidskriftsartikel (refereegranskat)abstract
- Many countries are raising the age of pension eligibility because of increases in life expectancy. Given the social gradient in life expectancy and health, it is important to understand the potential late-life health effects of prolonging working life and whether any effects differ by socioeconomic position. We examined the effect of prolonging working life beyond age 65 on mortality and a series of indicators of late-life physical health (the ability to climb stairs without difficulty, self-rated health, ADL limitations, and musculoskeletal pain) in a representative sample of the Swedish population. In addition to average effects, we also examined heterogeneous effects, for instance by occupational social class. To do this, we use propensity score matching, a method suitable for addressing causality in observational data. The data came from two linked Swedish longitudinal surveys based on nationally representative samples with repeated follow-ups; The Swedish Level of Living Survey and the Swedish Panel Study of Living conditions of the Oldest Old, and from national income and mortality registries. The analytical sample for the mortality outcome included 1852 people, and for late-life physical health outcomes 1461 people. We found no significant average treatment effect on the treated (ATT) of working to age 66 or above on the outcomes, measured an average of 12 years after retirement: mortality (ATT-0.039), the ability to climb stairs (ATT -0.023), self-rated health (ATT -0.009), ADL limitations (ATT -0.023), or musculoskeletal pain (ATT -0.009) in late life. Analyses of whether the results varied by occupational social class or the propensity to prolong working life were inconclusive but suggest a positive effect of prolonging working life on health outcomes. Accordingly, more detailed knowledge about the precise mechanisms underlying these results are needed. In conclusion, working to age 66 or above did not have effect on mortality or late-life physical health.
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| 36. |
- Fritzell, Johan, et al.
(författare)
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Trends and Inequality in the New Active Ageing and Well-Being Index of the Oldest Old : a Case Study of Sweden
- 2021
-
Ingår i: Journal of Population Ageing. - : Springer Science and Business Media LLC. - 1874-7884 .- 1874-7876. ; 14:5, s. 5-22
-
Tidskriftsartikel (refereegranskat)abstract
- The policy discourse on active ageing and well-being at the European level tends to have a strong focus on the experiences of the 'young old'. In this study the focus instead is on the oldest old (75 years and older). The theoretical framework is inspired by the Active Ageing Index and the Nordic welfare research tradition. Active ageing and well-being indicators and domains of high relevance for the oldest old are used and a new Active Ageing-Well Being Index (AA-WB Index) is developed. Our aim is to go beyond averages and analyse changes over time and inequality in the AA-WB Index. The prime data is derived from two waves, 2004 and 2014, of the Swedish Panel Study of Living Conditions of the Oldest Old (SWEOLD), a nationally representative sample of older people. The results show an overall improvement in most domains of the AA-WB index, especially in the indicator participation in cultural and leisure activities. The findings also show clear and consistent gender and educational inequalities. In addition, the different domains correlate, implying that inequality within a domain is aggravated by the inequality in another domain. The study highlights that measurements on active ageing and well-being should place a greater importance on the living conditions of the oldest old with a special focus on inequality.
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| 37. |
- Heap, Josephine, et al.
(författare)
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Associations between and coexistence of disadvantages in the oldest old people in Sweden : Patterns of change between 1992 and 2011
- 2018
-
Ingår i: Journal of European Social Policy. - : SAGE Publications. - 0958-9287 .- 1461-7269. ; 28:3, s. 197-210
-
Tidskriftsartikel (refereegranskat)abstract
- This study explored changes in the associations between and coexistence of disadvantages in several dimensions of living conditions in the oldest old people in Sweden. We used nationally representative data from 1992 (n = 537), 2002 (n = 621) and 2011 (n = 931). Indicators of limited social resources, limited political resources, limited financial resources, psychological health problems, physical health problems and functional limitations were used. The probability of reporting coexisting disadvantages tended to increase and was particularly elevated in 2002. Physical health problems became more common, and functional limitations, limited financial resources and limited political resources became less common during the studied period. Associations between health-related disadvantages remained fairly stable, whereas associations including other kinds of disadvantages varied somewhat over the studied period. These changes suggest that in general, the composition of coexisting disadvantages is likely to have altered over time. Consequently, the challenges faced by disadvantaged groups in 2011 may have been different from those in 1992. Moreover, the healthcare and social care services directed to older people have undergone significant changes during the past decades. These changes to the system accentuate the vulnerability of people experiencing coexisting disadvantages.
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| 38. |
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| 39. |
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| 40. |
- Heldin, Carl-Henrik, 1952-, et al.
(författare)
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Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
- 2018
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 283:1, s. 16-44
-
Forskningsöversikt (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.
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| 41. |
- Heldin, Carl-Henrik, et al.
(författare)
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Structural and functional properties of platelet-derived growth factor and stem cell factor receptors
- 2013
-
Ingår i: Cold Spring Harbor Perspectives in Biology. - : Cold Spring Harbor Laboratory. - 1943-0264. ; 5:8, s. UNSP a009100-
-
Tidskriftsartikel (refereegranskat)abstract
- The receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF) are members of the type III class of PTK receptors, which are characterized by five Ig-like domains extracellularly and a split kinase domain intracellularly. The receptors are activated by ligand-induced dimerization, leading to autophosphorylation on specific tyrosine residues. Thereby the kinase activities of the receptors are activated and docking sites for downstream SH2 domain signal transduction molecules are created; activation of these pathways promotes cell growth, survival, and migration. These receptors mediate important signals during the embryonal development, and control tissue homeostasis in the adult. Their overactivity is seen in malignancies and other diseases involving excessive cell proliferation, such as atherosclerosis and fibrotic diseases. In cancer, mutations of PDGF and SCF receptors-including gene fusions, point mutations, and amplifications-drive subpopulations of certain malignancies, such as gastrointestinal stromal tumors, chronic myelomonocytic leukemia, hypereosinophilic syndrome, glioblastoma, acute myeloid leukemia, mastocytosis, and melanoma.
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| 42. |
- Hou, Xu, et al.
(författare)
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PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets
- 2010
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:27, s. 12216-12221
-
Tidskriftsartikel (refereegranskat)abstract
- The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of the emerging drug resistance to anti-VEGF therapies. PDGF-CC is the third member of the PDGF family discovered after more than two decades of studies on PDGF-AA and PDGF-BB. The biological function of PDGF-CC and the underlying cellular and molecular mechanisms remain largely unexplored. Here, using different animal models, we report that PDGF-CC inhibition by neutralizing antibody, shRNA, or genetic deletion suppressed both choroidal and retinal neovascularization. Importantly, we revealed that PDGF-CC targeting acted not only on multiple cell types important for pathological angiogenesis, such as vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells, but also on the expression of other important angiogenic genes, such as PDGF-BB and PDGF receptors. At a molecular level, we found that PDGF-CC regulated glycogen synthase kinase (GSK)-3beta phosphorylation and expression both in vitro and in vivo. Activation of GSK3beta impaired PDGF-CC-induced angiogenesis, and inhibition of GSK3beta abolished the antiangiogenic effect of PDGF-CC blockade. Thus, we identified PDGF-CC as an important candidate target gene for antiangiogenic therapy, and PDGF-CC inhibition may be of therapeutic value in treating neovascular diseases.
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| 43. |
- Hägg, Maria, et al.
(författare)
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EGF and dextran-conjugated EGF induces differential phosphorylation of the EGF receptor
- 2002
-
Ingår i: International Journal of Molecular Medicine. - 1107-3756 .- 1791-244X. ; 10:5, s. 655-659
-
Tidskriftsartikel (refereegranskat)abstract
- Dextran-conjugated EGF (EGF-dextran) has a potential use for targeted radionuclide therapy of tumors that overexpress the epidermal growth factor receptor (EGFR). There are plans to treat both bladder carcinomas and malignant gliomas with local injections of radiolabeled EGF-dextran since these tumors often express high levels of EGFR. In this report we show that EGF and EGF-dextran differentially activate the EGFR. In the human glioma cell line U-343, activation of the serine/threonine kinases Erk and Akt is identical upon stimulation with EGF or EGF-dextran. However, the effect on phospholipase Cgamma1 (PLCgamma1) phosphorylation differs. In cells stimulated with EGF-dextran, the PLCgamma1 phosphorylation is lower than in cells stimulated with EGF. This observation could be explained by the fact that the PLCgamma1 association sites in the EGFR, tyrosine residues 992 and 1173, were phosphorylated to a lower degree when the receptor was stimulated with EGF-dextran as compared to with EGF.
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| 44. |
- Häggblad Sahlberg, Sara, et al.
(författare)
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The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines
- 2012
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 40:1, s. 176-184
-
Tidskriftsartikel (refereegranskat)abstract
- The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204) by radiation was both dose- and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.
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| 45. |
- Johansson, Ann-Sofi, 1974-
(författare)
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RhoGTPase Signaling in Cell Polarity and Gene Regulation
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- RhoGTPases are proteins working as molecular switches as they bind and hydrolyze GTP. They are in their active conformation when GTP is bound and are then able to interact with their effector proteins, which relay the downstream signaling. When the GTP is hydrolyzed to GDP, the RhoGTPase is inactivated. RhoGTPases have been shown to be activated by a variety of stimuli and they are implicated in regulation of diverse cellular processes, including cell migration, cell cycle progression, establishment of cell polarity and transformation. We identified mammalian Par6 as a novel effector protein for the RhoGTPases Cdc42 and Rac1. The Caenorhabditis elegans homologue of Par6 had previously been shown to be essential for cell polarity development in the worm embryo. We found that endogenous Par6 colocalized with the tight junction protein ZO-1 in MDCKII epithelial cells. Par6 also interacted with mammalian Par3, another member of the par (for partitioning defective) gene family, first identified in C.elegans. Endogenous Par3 also localized to tight junctions in epithelial cells. This suggested that Par6 and Par3 are part of a complex regulating cell polarity also in mammalian cells. The interaction between Par6 and activated Cdc42 and Rac1 suggested a role for these RhoGTPases in the regulation of this complex.Co-expression of Par6 together with PKCζ, induced a dramatic change in cell morphology. The cells rounded up and long cellular extensions, resembling neurites, were formed. The ability to induce these changes in cell morphology was found to be dependent on the direct interaction between Par6 and PKCζ, as well as on the kinase activity of PKCζ. We observed that cells co-expressing mPar6C and PKCζ contained bundled microtubules and microtubules that hade been acetylated, indicating that the microtubules were stabilized. To investigate the roles of RhoGTPases in PDGF-induced gene expression we performed cDNA microarray analyses on AG01518 human foreskin fibroblasts in which we over-expressed the dominant negative forms of Cdc42, Rac1 and RhoA. We found that the expression of 16 genes, out of the 45 up-regulated by PDGF-BB, were inhibited ≥50% in the presence of dominant negative Cdc42, Rac1 or RhoA. 19 other genes were down-regulated by one or two of the dominant RhoGTPases. Our data implied that the expression of many PDGF-BB induced genes can be affected by RhoGTPase signaling. In conclusion, the work presented here has increased the knowledge of the involvement of RhoGTPase signaling in establishment of cell polarity and gene regulation.
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| 46. |
- Jurek, Aleksandra, et al.
(författare)
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Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation
- 2009
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 284:7, s. 4626-4634
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Tidskriftsartikel (refereegranskat)abstract
- MAPK phosphatases (MKPs) are dual specificity phosphatases that dephosphorylate and thereby inactivate MAPKs. In the present study, we provide evidence that platelet-derived growth factor BB (PDGF-BB) regulates MKP3 (DUSP6), which is considered to be a phosphatase highly selective for Erk. Intriguingly, we observed that Mek is positively regulated by MKP3, whereas Erk itself is negatively regulated. In addition, we found that activation of PDGF receptor alpha or beta leads to a rapid proteasomal degradation of MKP3 in a manner that requires Mek activation; this feed-forward mechanism was found to be essential for efficient Erk phosphorylation. We could also demonstrate that PDGF-BB stimulation induces phosphorylation of MKP3 at Ser-174 and Ser-300; phosphorylation of Ser-174 is involved in PDGF-induced MKP3 degradation, since mutation of this site stabilized MKP3. Moreover, activated Erk induces mkp3 expression, leading to restoration of MKP3 levels after 1-2 h and a concomitant dephosphorylation of Erk in cells with activated PDGFRalpha. Reducing the MKP3 level by small interfering RNA leads to an increased Erk activation and mitogenic response to PDGF-BB. In conclusion, MKP3 is an important regulator of PDGF-induced Erk phosphorylation acting in both a rapid positive feed-forward and a later negative feed-back loop.
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| 47. |
- Jurek, Aleksandra, et al.
(författare)
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Platelet-derived growth factor-induced signaling pathways interconnect to regulate the temporal pattern of Erk1/2 phosphorylation
- 2011
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 23:1, s. 280-287
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Tidskriftsartikel (refereegranskat)abstract
- The biological outcome of Erk1/2 activation is specified by the duration and magnitude of its phosphorylation, as well as its subcellular localization. In the present study, we investigated how the cross-talk between signaling pathways induced by platelet-derived growth factor receptor beta (PDGFR beta) regulates the temporal pattern of Erk1/2 activation. We demonstrated that Src kinase activity was necessary for rapid Erk1/2 phosphorylation in PDGF-BB-stimulated cells. A delay in the onset of Erk1/2 activation was also observed upon phospholipase C (PLC) inhibition; this effect was found to be mediated by protein kinase C (PKC). In addition, we observed that both the PI3K pathway and RasGAP negatively regulated the strength of Erk1/2 phosphorylation. In contrast, interfering with SHP2 binding to PDGFR beta did not affect the pattern of Erk1/2 activation. Interestingly, changes in the kinetics and amplitude of Erk1/2 activation were transmitted to the transcriptional level and affected c-fos expression. In conclusion, cross-talk with other PDGFR beta-induced signaling pathways is important for fine-tuning of the pattern of Erk1/2 activation.
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| 48. |
- Kalstad Lönne, Gry, et al.
(författare)
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Protein kinase Cdelta supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway
- 2009
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Ingår i: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology, Inc.. - 0021-9258 .- 1083-351X. ; 284:48, s. 33456-33465
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase Cdelta (PKCdelta) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKCdelta per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKCdelta-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKCdelta depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKCdelta down-regulation. However, PKCdelta silencing also induced increased MEK1/2 phosphorylation, indicating that PKCdelta regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKCdelta silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKCdelta as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.
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| 49. |
- Kermpatsou, Despoina, et al.
(författare)
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Cellular responses to silencing of PDIA3 (protein disulphide-isomerase A3) : Effects on proliferation, migration, and genes in control of active vitamin D
- 2024
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier. - 0960-0760 .- 1879-1220. ; 240
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Tidskriftsartikel (refereegranskat)abstract
- The active form of vitamin D, 1,25-dihydroxyvitamin D3, is known to act via VDR (vitamin D receptor), affecting several physiological processes. In addition, PDIA3 (protein disulphide-isomerase A3) has been associated with some of the functions of 1,25-dihydroxyvitamin D3. In the present study we used siRNA-mediated silencing of PDIA3 in osteosarcoma and prostate carcinoma cell lines to examine the role(s) of PDIA3 for 1,25-dihydroxyvitamin D3-dependent responses. PDIA3 silencing affected VDR target genes and significantly altered the 1,25-dihydroxyvitamin D3-dependent induction of CYP24A1, essential for elimination of excess 1,25-dihydroxyvitamin D3. Also, PDIA3 silencing significantly altered migration and proliferation in prostate PC3 cells, independently of 1,25-dihydroxyvitamin D3. 1,25-Dihydroxyvitamin D3 increased thermostability of PDIA3 in cellular thermal shift assay, supporting functional interaction between PDIA3 and 1,25-dihydroxyvitamin D3-dependent pathways. In summary, our data link PDIA3 to 1,25-dihydroxyvitamin D3-mediated signalling, underline and extend its role in proliferation and reveal a novel function in maintenance of 1,25-dihydroxyvitamin D3 levels.
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| 50. |
- Kermpatsou, Despoina, et al.
(författare)
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Silencing of 1,25D3-MARRS (membrane-associated, rapid response steroid-binding) receptor in prostate cancer cell lines PC3 and DU145: effects on cellular responses
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 1,25(OH)2-vitamin D3 has well-documented roles in a variety of cellular processes, including proliferation and differentiation. 1,25(OH)2-vitamin D3 signalling is largely mediated by vitamin D receptor (VDR), however, 1,25D3-MARRS (membrane-associated, rapid response steroid-binding) receptor has been investigated as a potential transducer of 1,25(OH)2-vitamin D3 membrane-initiated response. In this work we aimed to study the role of 1,25D3-MARRS in androgen-independent prostate carcinoma cell lines PC3 and DU145. Protein lysates from an array of cell lines were enriched for cytoplasmic and nuclear protein pools, in order to investigate the subcellular localisation of 1,25D3-MARRS and VDR. Further, we studied the effects of siRNA-mediated 1,25D3-MARRS depletion on cell proliferation and migration, as well as on gene expression of 1,25(OH)2-vitamin D3 metabolising enzymes and other genes of importance for 1,25(OH)2-vitamin D3-mediated signalling. The results of the present study indicate that depletion of 1,25D3-MARRS decreases proliferation in PC3 and DU145 prostate cancer cell lines, potentially via downregulation of c-Myc. 1,25D3-MARRS silencing also increased migration in PC3 cells, but not in DU145 cells, suggesting differential effects in different prostate cancer cell lines. In addition, significant effects of 1,25D3-MARRS silencing were found on CYP27B1 and CYP24A1, enzymes responsible for the regulation of cellular levels of 1,25(OH)2-vitamin D3. In summary, our data indicate that 1,25D3-MARRS can affect proliferation and/or migration in androgen-independent prostate cancer cells and may play a role for regulation and maintenance of adequate cellular 1,25(OH)2-vitamin D3 levels, either together with or independently of VDR.
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