| 1. |
- van der Ploeg, Milly A., et al.
(författare)
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Patient Characteristics and General Practitioners' Advice to Stop Statins in Oldest-Old Patients : a Survey Study Across 30 Countries
- 2019
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Ingår i: Journal of general internal medicine. - : Springer. - 0884-8734 .- 1525-1497. ; 34:9, s. 1751-1757
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Tidskriftsartikel (refereegranskat)abstract
- Background Statins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners' (GPs) advice to stop statins in oldest-old patients. Objective To investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs' advice to stop statins in oldest-old patients. Design We invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment. Main Measures Cases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs' advice to stop. Key Results Two thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45-47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89-90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6-15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5-1.7) and with frailty (ORadj 4.1, 95%CI 3.8-4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5-56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19-42) to 98% (95% CI 96-99). Conclusions The absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs' advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs' advice to stop statins.
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| 2. |
- Bojmar, Linda, et al.
(författare)
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Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
- 2024
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Ingår i: Nature Medicine. - : NATURE PORTFOLIO. - 1078-8956 .- 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B(+) natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B(+) NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.<br />
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| 3. |
- Streit, Sven, et al.
(författare)
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Burden of cardiovascular disease across 29 countries and GPs' decision to treat hypertension in oldest-old.
- 2018
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Ingår i: Scandinavian Journal of Primary Health Care. - : Taylor & Francis. - 0281-3432 .- 1502-7724. ; 36:1, s. 89-98
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We previously found large variations in general practitioner (GP) hypertension treatment probability in oldest-old (>80 years) between countries. We wanted to explore whether differences in country-specific cardiovascular disease (CVD) burden and life expectancy could explain the differences.DESIGN: This is a survey study using case-vignettes of oldest-old patients with different comorbidities and blood pressure levels. An ecological multilevel model analysis was performed.SETTING: GP respondents from European General Practice Research Network (EGPRN) countries, Brazil and New Zeeland.SUBJECTS: This study included 2543 GPs from 29 countries.MAIN OUTCOME MEASURES: GP treatment probability to start or not start antihypertensive treatment based on responses to case-vignettes; either low (<50% started treatment) or high (≥50% started treatment). CVD burden is defined as ratio of disability-adjusted life years (DALYs) lost due to ischemic heart disease and/or stroke and total DALYs lost per country; life expectancy at age 60 and prevalence of oldest-old per country.RESULTS: Of 1947 GPs (76%) responding to all vignettes, 787 (40%) scored high treatment probability and 1160 (60%) scored low. GPs in high CVD burden countries had higher odds of treatment probability (OR 3.70; 95% confidence interval (CI) 3.00-4.57); in countries with low life expectancy at 60, CVD was associated with high treatment probability (OR 2.18, 95% CI 1.12-4.25); but not in countries with high life expectancy (OR 1.06, 95% CI 0.56-1.98).CONCLUSIONS: GPs' choice to treat/not treat hypertension in oldest-old was explained by differences in country-specific health characteristics. GPs in countries with high CVD burden and low life expectancy at age 60 were most likely to treat hypertension in oldest-old. Key Points • General practitioners (GPs) are in a clinical dilemma when deciding whether (or not) to treat hypertension in the oldest-old (>80 years of age). • In this study including 1947 GPs from 29 countries, we found that a high country-specific cardiovascular disease (CVD) burden (i.e. myocardial infarction and/or stroke) was associated with a higher GP treatment probability in patients aged >80 years. • However, the association was modified by country-specific life expectancy at age 60. While there was a positive association for GPs in countries with a low life expectancy at age 60, there was no association in countries with a high life expectancy at age 60. • These findings help explaining some of the large variation seen in the decision as to whether or not to treat hypertension in the oldest-old.
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| 4. |
- Streit, Sven, et al.
(författare)
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Variation in GP decisions on antihypertensive treatment in oldest-old and frail individuals across 29 countries.
- 2017
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Ingår i: BMC Geriatrics. - : BioMed Central. - 1471-2318. ; 17:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.METHODS: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.RESULTS: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs' decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48-0.59; ORs per country 0.11-1.78).CONCLUSIONS: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
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| 5. |
- Burman, Robert, et al.
(författare)
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Chemistry and Biology of Cyclotides : Circular Plant Peptides Outside the Box
- 2014
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Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 77:3, s. 724-736
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Forskningsöversikt (refereegranskat)abstract
- Cyclotides stand out as the largest family of circular proteins of plant origin hitherto known, with more than 280 sequences isolated at peptide level and many more predicted from gene sequences. Their unusual stability resulting from the signature cyclic cystine knot (CCK) motif has triggered a broad interest in these molecules for potential therapeutic and agricultural applications. Since the time of the first cyclotide discovery, our laboratory in Uppsala has been engaged in cyclotide discovery as well as the development of protocols to isolate and characterize these seamless peptides. We have also developed methods to chemically synthesize cyclotides by Fmoc-SPPS, which are useful in protein grafting applications. In this review, experience in cyclotide research over two decades and the recent literature related to their structures, synthesis, and folding as well the recent proof-of-concept findings on their use as "epitope" stabilizing scaffolds are summarized.
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| 6. |
- Burman, Robert, et al.
(författare)
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Cyclotide-membrane interactions: defining factors of membrane binding, depletion and disruption
- 2011
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Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier BV. - 0005-2736 .- 1879-2642. ; 1808:11, s. 2665-2673
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Tidskriftsartikel (refereegranskat)abstract
- The cyclotide family of plant-derived peptides is defined by a cyclic backbone and three disulfide bonds locked into a cyclic cystine knot. They display a diverse range of biological activities, many of which have been linked to an ability to target biological membranes. In the current work, we show that membrane binding and disrupting properties of prototypic cyclotides are dependent on lipid composition, using neutral (zwitterionic) membranes with or without cholesterol and/or anionic lipids. Cycloviolacin O2 (cyO2) caused potent membrane disruption, and showed selectivity towards anionic membranes, whereas kalata B1 and kalata B2 cyclotides were significantly less lytic towards all tested model membranes. To investigate the role of the charged amino acids of cyO2 in the membrane selectivity, these were neutralized using chemical modifications. In contrast to previous studies on the cytotoxic and antimicrobial effects of these derivatives, the Glu6 methyl ester of cyO2 was more potent than the native peptide. However, using membranes of Escherichia coil lipids gave the opposite result: the activity of the native peptide increased 50-fold. By using a combination of ellipsometry and LC-MS, we demonstrated that this unusual membrane specificity is due to native cyO2 extracting preferentially phosphatidylethanolamine-lipids from the membrane, i.e., PE-C16:0/cyC17:0 and PE-C16:0/C18:1.
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| 7. |
- Burman, Robert, 1979-, et al.
(författare)
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Membrane integrity as a target for cyclotide cytotoxic activity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The cyclotides are a family of plant-derived proteins that occur in plants from the Violaceae (violet) and Rubiaceae (coffee) families and have a diverse range of biological activities, including cytotoxic, hemolytic, antimicrobial, and insecticidal activities; the latter suggests their natural function lies in plant defense. In the current study we have investigated the membrane-disrupting and adsorption ability of prototypic cyclotides and correlated these findings to their cytotoxic properties. We also included modifications of selected charged amino acids in cycloviolacin O2, previously shown to be of importance for its cytotoxic activity. The cyclotides’ cytotoxic activity, ability to adsorb and disrupt model lipid membranes of different charge densities was investigated, e.g. by fluorescence spectroscopy, ellipsometry, and circular dichroism. Cytotoxicity of the native cyclotides was demonstrated to correlate to membrane adsorption and lytic activity. Hence, the activity of native cyclotides is mainly due to interactions between the proteins and the phospholipids in the target membrane. Striking effects of single amino acid variations in cycloviolacin O2 on its membrane interaction were also demonstrated.
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| 8. |
- Fransson, Moa, et al.
(författare)
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CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery
- 2012
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 9, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naive CD4 cells and demonstrate their efficacy in the EAE model.METHODSCD4+T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.RESULTSThe engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptomfree mice were echallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.CONCLUSIONCNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.
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| 9. |
- Fransson, Moa, et al.
(författare)
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Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis
- 2014
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 142:3, s. 431-441
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with mesenchymal stromal cells (MSC) is currently of interest for a number of diseases including multiple sclerosis (MS). MSCs is well known to target inflamed tissues however, in a therapeutic scenery, systemic administration will lead to few cells reaching the brain. We hypothesized that MSCs may target the brain upon intranasal (i.n) administration and persist in CNS tissue if expressing a CNS-targeting receptor. To demonstrate proof of concept, MSCs were genetically engineered to express a myelin oligodendrocyte glycoprotein (MOG)-specific receptor. Engineered MSCs retained their immunosuppressive capacity, infiltrated into the brain upon i.n. cell administration, and were able to significantly reduce disease symptoms of experimental autoimmune encephalomyelitis (EAE). The mice treated with CNS-targeting MSCs were resistant to further EAE induction whereas non-targeted MSC did not give such persistent effects. Histological analysis revealed increased brain restoration in engineered MSC-treated mice. In conclusion, MSCs can be genetically engineered to target the brain and prolong therapeutic efficacy in an EAE model.
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| 10. |
- Göransson, Ulf, et al.
(författare)
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Circular Proteins from Plants and Fungi
- 2012
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:32, s. 27001-27006
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Forskningsöversikt (refereegranskat)abstract
- Circular proteins, defined as head-to-tail cyclized polypeptides originating from ribosomal synthesis, represent a novel class of natural products attracting increasing interest. From a scientific point of view, these compounds raise questions of where and why they occur in nature and how they are formed. From a rational point of view, these proteins and their structural concept may be exploited for crop protection and novel pharmaceuticals. Here, we review the current knowledge of three protein families: cyclotides and circular sunflower trypsin inhibitors from the kingdom of plants and the Amanita toxins from fungi. A particular emphasis is placed on their biological origin, structure, and activity. In addition, the opportunity for discovery of novel circular proteins and recent insights into their mechanism of action are discussed.
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