| 1. |
- König, Nico, et al.
(author)
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Spherical Micelles with Nonspherical Cores : Effect of Chain Packing on the Micellar Shape
- 2020
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In: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; , s. 10686-10698
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Journal article (peer-reviewed)abstract
- Self-assembly of amphiphilic polymers into micelles is an archetypical example of a "self-confined"system due to the formation of micellar cores with dimensions of a few nanometers. In this work, we investigate the chain packing and resulting shape of Cn-PEOx micelles with semicrystalline cores using small/wide-angle X-ray scattering (SAXS/WAXS), contrast-variation small-angle neutron scattering (SANS), and nuclear magnetic resonance spectroscopy (NMR). Interestingly, the n-alkyl chains adopt a rotator-like conformation and pack into prolate ellipses (axial ratio ϵ ≈ 0.5) in the "crystalline"region and abruptly arrange into a more spheroidal shape (ϵ ≈ 0.7) above the melting point. We attribute the distorted spherical shape above the melting point to thermal fluctuations and intrinsic rigidity of the n-alkyl blocks. We also find evidence for a thin dehydrated PEO layer (≤1 nm) close to the micellar core. The results provide substantial insight into the interplay between crystallinity and molecular packing in confinement and the resulting overall micellar shape.
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| 2. |
- Lund, Mikael, et al.
(author)
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Effects of neoadjuvant chemo or chemoradiotherapy for oesophageal cancer on perioperative haemodynamics A prospective cohort study within a randomised clinical trial
- 2016
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In: European Journal of Anaesthesiology. - : Lippincott Williams & Wilkins. - 0265-0215 .- 1365-2346. ; 33:9, s. 653-661
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Journal article (peer-reviewed)abstract
- BACKGROUND Neoadjuvant chemoradiotherapy might improve oncological outcome compared with chemotherapy after surgery for oesophagus or gastrooesophageal junction cancer. However, radiotherapy may induce cardiovascular side-effects that could increase the risk of perioperative adverse effects and postoperative morbidity. OBJECTIVES The aim of this study was to compare the perioperative haemodynamics in patients undergoing oesophagectomy following neoadjuvant chemotherapy or chemoradiotherapy for cancer. DESIGN A prospective single-centre cohort study within a randomised multi-centre trial. SETTING A Swedish University Hospital from January 2009 to March 2013. PATIENTS A total of 31 patients (chemotherapy 17, chemoradiotherapy 14) included in a multi-centre trial randomising chemotherapy vs. chemoradiotherapy and operated at Karolinska University Hospital, Huddinge. INTERVENTIONS Cisplatin and 5-fluorouracil, either with or without concurrent radiotherapy (40 Gy), were given prior to surgery. Cardiac function was assessed with LiDCOplus (LiDCO Ltd, London, United Kingdom), echocardiography, troponin T and N-terminal pro-B-type natriuretic peptide, before, during and after surgery. MAIN OUTCOME MEASURES The primary outcome was the interaction effect of the neoadjuvant treatment on stroke volume index during the perioperative period. Secondary outcomes were the interaction effects of oxygen delivery index, cardiac index, echocardiography and biochemical markers. RESULTS The groups were matched regarding comorbidities, but patients in the chemoradiotherapy group were older (66 vs. 60 years P = 0.03). Haemodynamic values changed in a similar way in both groups during the study period. The chemoradiotherapy group had a lower cardiac index before surgery (2.9 vs. 3.4 l min(-1) m(-2), P = 0.03). On the third postoperative day, both groups displayed a hyperdynamic state compared with baseline, with no increase in troponin T, and a similar increase in N-terminal pro-B-type natriuretic peptide. CONCLUSION Neoadjuvant chemoradiotherapy for oesophageal or gastrooesophageal junction cancer seems to induce only a marginal negative effect on cardiac function compared with neoadjuvant chemotherapy. This difference did not remain when patients' haemodynamics were challenged by surgery.
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| 3. |
- Lund, Mikael, et al.
(author)
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Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction : a prospective cohort pilot study within a randomized clinical trial
- 2015
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In: Radiation Oncology. - : Springer Science and Business Media LLC. - 1748-717X. ; 10
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Journal article (peer-reviewed)abstract
- Background: Neoadjuvant therapy for cancer of the esophagus or gastroesophageal (GE)-junction is well established. The pros and cons of chemoradiotherapy and chemotherapy are debated. Chemoradiotherapy might impair cardiac function eliciting postoperative morbidity. The aim of this pilot study was to describe acute changes in left ventricular function following chemoradiotherapy or chemotherapy. Methods: Patients with esophageal and (GE)-junction cancer enrolled at our center into a multicenter trial comparing neoadjuvant chemoradiotherapy and chemotherapy were eligible. Patients were randomized to receive cisplatin and 5-fluorouracil with or without the addition of 40 Gy radiotherapy prior to surgery. Left ventricular function was evaluated using echocardiography and plasma N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) before and after neoadjuvant treatment. The primary outcome measure was left ventricular global strain (GS). Clinical effects were assessed using repeated exercise tests. Linear mixed models were used to analyze the effects of treatment group, and the interaction between groups. Results: 40 patients participated (chemoradiotherapy, n = 17; chemotherapy, n = 23). In the chemoradiotherapy group there was no change in left ventricular global strain but mitral annular plane systolic excursion (MAPSE) of the ventricular septum, early diastolic filling velocity (E-velocity), and the ratio of early to late ventricular filling velocities (E/A ratio) decreased significantly (p = 0.02, p = 0.01, and p = 0.03, respectively). No changes were observed in the chemotherapy group. There was a trend towards an interaction effect for MAPSE sept and E (p = 0.09 and p = 0.09). NT-proBNP increased following chemoradiotherapy (p = 0.05) but not after chemotherapy (p > 0.99), and there was a trend towards an interaction effect (p = 0.07). Working capacity decreased following neoadjuvant treatment (chemoradiotherapy p = 0.001, chemotherapy p = 0.03) and was more pronounced after chemoradiotherapy with a trend towards an interaction effect (p = 0.10). Conclusions: Neoadjuvant chemoradiotherapy but not chemotherapy before surgery for cancer of the esophagus or GE-junction seems to induce an acute negative effect on both systolic and diastolic left ventricular function. Future studies on neoadjuvant treatment for esophageal cancer are suggested to add measurements of cardiac function.
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| 4. |
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| 5. |
- Maric, Selma, et al.
(author)
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Time-resolved small-angle neutron scattering as a probe for the dynamics of lipid exchange between human lipoproteins and naturally derived membranes
- 2019
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- Atherosclerosis is the main killer in the western world. Today's clinical markers include the total level of cholesterol and high-/low-density lipoproteins, which often fails to accurately predict the disease. The relationship between the lipid exchange capacity and lipoprotein structure should explain the extent by which they release or accept lipid cargo and should relate to the risk for developing atherosclerosis. Here, small-angle neutron scattering and tailored deuteration have been used to follow the molecular lipid exchange between human lipoprotein particles and cellular membrane mimics made of natural, "neutron invisible" phosphatidylcholines. We show that lipid exchange occurs via two different processes that include lipid transfer via collision and upon direct particle tethering to the membrane, and that high-density lipoprotein excels at exchanging the human-like unsaturated phosphatidylcholine. By mapping the specific lipid content and level of glycation/oxidation, the mode of action of specific lipoproteins can now be deciphered. This information can prove important for the development of improved diagnostic tools and in the treatment of atherosclerosis.
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| 6. |
- Narayanan, Theyencheri, et al.
(author)
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Recent applications of synchrotron radiation and neutrons in the study of soft matter
- 2017
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In: Crystallography Reviews. - 0889-311X. ; 23:3, s. 160-226
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Research review (peer-reviewed)abstract
- The broad range of applications of synchrotron and neutron scattering in the investigation of soft condensed matter is reviewed. Appropriate combinations of these techniques allow probing the structure and dynamics of these complex systems from sub-nm to micron size scales and picoseconds to seconds and longer time ranges. Applications include a myriad of systems such as polymers, colloids, surfactants, phospholipids, biological macromolecules and functional materials both in bulk and at interfaces. Most studies are performed in situ under the real thermodynamic state of the given system and large ensemble averaged information is readily obtained. The new generations of synchrotron and neutron sources open possibilities for investigating more complex soft matter systems in hitherto unexplored dynamical states.
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| 7. |
- Nielsen, Josefine Eilsø, et al.
(author)
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A biophysical study of the interactions between the antimicrobial peptide indolicidin and lipid model systems
- 2019
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In: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier. - 0005-2736 .- 1879-2642. ; 1861:7, s. 1355-1364
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Journal article (peer-reviewed)abstract
- The naturally occurring peptide indolicidin from bovine neutrophils exhibits strong biological activity against a broad spectrum of microorganisms. This is believed to arise from selective interactions with the negatively charged cytoplasmic lipid membrane found in bacteria. We have investigated the peptide interaction with supported lipid model membranes using a combination of complementary surface sensitive techniques: neutron reflectometry (NR), atomic force microscopy (AFM), and quartz crystal microbalance with dissipation monitoring (QCM-D). The data are compared with small-angle X-ray scattering (SAXS) results obtained with lipid vesicle/peptide solutions. The peptide membrane interaction is shown to be significantly concentration dependent. At low concentrations, the peptide inserts at the outer leaflet in the interface between the headgroup and tail core. Insertion of the peptide results in a slight decrease in the lipid packing order of the bilayer, although not sufficient to cause membrane thinning. By increasing the indolicidin concentration well above the physiologically relevant conditions, a deeper penetration of the peptide into the bilayer and subsequent lipid removal take place, resulting in a slight membrane thinning. The results suggest that indolicidin induces lipid removal and that mixed indolicidin-lipid patches form on top of the supported lipid bilayers. Based on the work presented using model membranes, indolicidin seems to act through the interfacial activity model rather than through the formation of stable pores.
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| 8. |
- Nielsen, Josefine Eilsø, et al.
(author)
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Lipid membrane interactions of self-assembling antimicrobial nanofibers : effect of PEGylation
- 2020
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In: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 10, s. 35329-35340
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Journal article (peer-reviewed)abstract
- Supramolecular assembly and PEGylation (attachment of a polyethylene glycol polymer chain) of peptides can be an effective strategy to develop antimicrobial peptides with increased stability, antimicrobial efficacy and hemocompatibility. However, how the self-assembly properties and PEGylation affect their lipid membrane interaction is still an unanswered question. In this work, we use state-of-the-art small angle X-ray and neutron scattering (SAXS/SANS) together with neutron reflectometry (NR) to study the membrane interaction of a series of multidomain peptides, with and without PEGylation, known to self-assemble into nanofibers. Our approach allows us to study both how the structure of the peptide and the membrane are affected by the peptide–lipid interactions. When comparing self-assembled peptides with monomeric peptides that are not able to undergo assembly due to shorter chain length, we found that the nanofibers interact more strongly with the membrane. They were found to insert into the core of the membrane as well as to absorb as intact fibres on the surface. Based on the presented results, PEGylation of the multidomain peptides leads to a slight net decrease in the membrane interaction, while the distribution of the peptide at the interface is similar to the non-PEGylated peptides. Based on the structural information, we showed that nanofibers were partially disrupted upon interaction with phospholipid membranes. This is in contrast with the considerable physical stability of the peptide in solution, which is desirable for an extended in vivo circulation time.
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| 11. |
- Sahlen, Anders, et al.
(author)
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Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients
- 2011
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In: American Journal of Physiology. Heart and Circulatory Physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 301:6, s. H2433-H2441
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Journal article (peer-reviewed)abstract
- Sahlen A, Abdula G, Norman M, Manouras A, Brodin LA, Lund LH, Shahgaldi K, Winter R. Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients. Am J Physiol Heart Circ Physiol 301: H2433-H2441, 2011. First published September 16, 2011; doi:10.1152/ajpheart.00555.2011.-Elderly female hypertensives with arterial stiffening constitute a majority of patients with heart failure with preserved ejection fraction (HFpEF), a condition characterized by inability to increase cardiac stroke volume (SV) with physical exercise. As SV is determined by the interaction between the left ventricle (LV) and its load, we wished to study the role of arterial hemodynamics for exertional SV reserve in patients at high risk of HFpEF. Twenty-one elderly (67 +/- 9 yr) female hypertensive patients were studied at rest and during supine bicycle stress using echocardiography including pulsed-wave Doppler to record flow in the LV outflow tract and arterial tonometry for central arterial pressure waveforms. Arterial compliance was estimated based on an exponential relationship between pressure and volume. The ratio of aortic pressure-to-flow in early systole was used to derive characteristic impedance, which was subsequently subtracted from total resistance (mean arterial pressure/cardiac output) to yield systemic vascular resistance (SVR). It was found that patients with depressed SV reserve (NoRes; reserve <15%; n = 10) showed decreased arterial compliance during exercise, while patients with SV reserve >= 15% (Res; n = 11) showed increased compliance. Exercise produced parallel increases in LV end-diastolic volume and arterial volume in Res patients while NoRes patients exhibited a lesser decrease in SVR and a drop in effective arterial volume. Poor SV reserve in elderly female hypertensives is due to simultaneous failure of LV preload and arterial vasodilatory reserves. Abnormal arterial function contributes to a high risk of HFpEF in these patients.
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| 12. |
- Venkateshvaran, Ashwin, et al.
(author)
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The impact of arterial load on left ventricular performance : An invasive haemodynamic study in severe mitral stenosis
- 2015
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 593:8, s. 1901-1912
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Journal article (peer-reviewed)abstract
- Key points: A hallmark of mitral stenosis (MS) is the markedly altered left ventricular (LV) loading. As most of the methods used to determine LV performance in MS patients are influenced by loading conditions, previous studies have shown conflicting results. The present study calculated LV elastance, which is a robust method to quantify LV function. We demonstrate that LV loading in MS patients is elevated but normalizes after valve repair and might be a result of reflex pathways. Additionally, we show that the LV in MS is less compliant than normal due to a combination of right ventricular loading and the valvular disease itself. Immediately after valve dilatation the increase in blood inflow into the LV results in even greater LV stiffness. Our findings enrich our understanding of heart function in MS patients and provide a simple reproducible way of assessing LV performance in MS. Left ventricular (LV) function in rheumatic mitral stenosis (MS) remains an issue of controversy, due to load dependency of previously employed assessment methods. We investigated LV performance in MS employing relatively load-independent indices robust to the altered loading state. We studied 106 subjects (32 ± 8 years, 72% female) with severe MS (0.8 ± 0.2 cm2) and 40 age-matched controls. MS subjects underwent simultaneous bi-ventricular catheterization and transthoracic echocardiography (TTE) before and immediately after percutaneous transvenous mitral commisurotomy (PTMC). Sphygmomanometric brachial artery pressures and TTE recordings were simultaneously acquired in controls. Single-beat LV elastance (Ees) was employed for LV contractility measurements. Effective arterial elastance (Ea) and LV diastolic stiffness were measured. MS patients demonstrated significantly elevated afterload (Ea: 3.0 ± 1.3 vs. 1.5 ± 0.3 mmHg ml-1; P < 0.001) and LV contractility (Ees: 4.1 ± 1.6 vs. 2.4 ± 0.5 mmHg ml-1; P < 0.001) as compared to controls, with higher Ea in subjects with smaller mitral valve area (≤ 0.8 cm2) and pronounced subvalvular fusion. Stroke volume (49 ± 16 to 57 ± 17 ml; P < 0.001) and indexed LV end-diastolic volume (LVEDVindex: 57 ± 16 to 64 ± 16 ml m-2; P < 0.001) increased following PTMC while Ees and Ea returned to more normal levels. Elevated LV stiffness was demonstrated at baseline and increased further following PTMC. Our findings provide evidence of elevated LV contractility, increased arterial load and increased diastolic stiffness in severe MS. Following PTMC, both LV contractility and afterload tend to normalize.
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