Polyethylene glycol (PEG)-conjugated lipids are commonly employed for steric stabilization of liposomes. When added in high concentrations PEG-lipids induce formation of mixed micelles, and depending ...on the lipid composition of the sample, these may adapt either a discoidal or a long threadlike shape. The factors governing the type of micellar aggregate formed have so far not been investigated in detail. In this study we have systematically varied the lipid composition in lipid/PEG-lipid mixtures and characterized the aggregate structure by means of cryo-transmission electron microscopy (cryo-TEM). The effects caused by adding sterols, phosphatidylethanolamines, and phospholipids with saturated acyl chains to egg phosphatidylcholine/1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-methoxy(polyethylene glycol)-2000 (EPC/DSPE-PEG2000) mixtures with a fixed amount (25 mol %) of DSPE-PEG2000 was studied. Further, the aggregate structure in 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine/1,2-dimyristoyl-sn-glycero-3-phosphatidylethanolamine-N-methoxy(polyethylene glycol)-2000 (DMPC/DMPE-PEG2000) samples above and below the gel to liquid crystalline phase transition temperature (T C) was investigated. Our results revealed that lipid components, as well as environmental conditions, that reduce the lipid spontaneous curvature and increase the monolayer bending modulus tend to promote formation of discoidal micelles. At temperatures below the gel-to-liquid crystalline phase transition temperature reduced lipid/PEG-lipid miscibility, furthermore, likely contribute to the observed formation of discoidal rather than threadlike micelles.
Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, ...sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow‐up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri‐menopausal women, 111 in post‐menopausal women, and 70 in men) and 706 cancer‐free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre‐menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96–2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96–3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28–1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post‐menopausal women and men but may suggest an involvement of altered sex steroid production in pre‐menopausal women.
What's new?
Thyroid cancer occurs more often in women than men, suggesting that sex hormones may contribute to the disease. Here, the authors investigated the association between circulating sex steroid hormones, sex hormone binding globulin protein (SHBG), and the risk of thyroid cancer in both men and women using data from the European Prospective Investigation into Cancer and nutrition (EPIC). They measured concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre‐menopausal women only), as well as SHBG. Overall, they did not detect a strong association between hormones, SHBG and thyroid cancer incidence.
In a recent study we showed that the surfactant 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-PEG(2000)) induce mixed micelles of either threadlike or ...discoidal shape when mixed with different types of lipids. In certain lipid systems the discoidal micelles adapt sizes large enough to be characterized as bilayer discs. The discs hold great potential for use in various biotechnical applications and may e.g. be used as model membranes in drug/membrane partition studies. Depending on the application, discs with certain characteristics, such as a particular size or size homogeneity, may be required. These factors can in our experience be influenced by the preparation method. In this study we systematically investigated three different PEG-lipid/lipid mixtures prepared by four commonly used preparation techniques. The techniques used were simple hydration, freeze-thawing, sonication and detergent depletion, and the aggregate size and structure was analyzed by cryo transmission electron microscopy (cryo-TEM) and dynamic light scattering (DLS). Our results show that the type and size of the micellar structure found, as well as the structure homogeneity of the preparation, can be modified by the choice of preparation path.
Background
Dietary pattern analysis has gained particular interest, because it reflects the complexity of dietary intake. The aim of this study was to explore the associations between a posteriori ...dietary patterns, derived using a data-driven approach, and the risk of differentiated thyroid cancer (TC) in Europe.
Methods
This investigation included 450,064 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Dietary intake was assessed using validated country-specific dietary questionnaires. A posteriori dietary patterns were computed using principal component analyses. Cox regression was used to calculate multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results
After a mean follow-up time of 14 years, 712 first differentiated TCs were diagnosed. In the fully adjusted model, a dietary pattern characterized by alcohol consumption (basically beer and wine) was negatively associated with differentiated TC risk (HR
Q4vs.Q1
= 0.75; 95% CI:0.60–0.94,
P
-trend = 0.005), while a dietary pattern rich in sweetened beverages was positively associated with differentiated TC risk (HR
Q4vs.Q1
= 1.26; 95% CI:0.99–1.61;
P
-trend = 0.07). The remaining 8 dietary patterns were not related to differentiated TC risk. The intake of sweetened beverages was positively associated with differentiated TC risk (HR
100mL/d
= 1.05; 95% CI:1.00–1.11), especially with papillary TC risk (HR
100mL/d
= 1.07; 95% CI:1.01–1.13). Similar results were observed with sugary and artificially sweetened beverages.
Conclusions
The investigation of dietary patterns detected that the consumption of sweetened beverages was associated with a higher risk of differentiated thyroid cancer. Our results are in line with the general dietary recommendations of reducing the consumption of sweetened beverages.
The Mediterranean diet (MD) has been proposed as a healthy diet with a potential to lower the incidence of several types of cancer, but there is no data regarding thyroid cancer (TC). We investigated ...the association between MD adherence, and its components, and the differentiated TC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.
Over 450,000 men and women from nine European countries were followed up for a mean of 14.1 years, during which 712 differentiated TC cases were identified. Adherence to MD was estimated using the relative MD (rMED) score, an 18-point scale including alcohol, and the adapted rMED (arMED) score, a 16-point scale excluding alcohol. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors.
Adherence to the arMED score was not associated with the risk of differentiated TC (HR
= 0.94, 95% CI: 0.70-1.25;
-trend 0.27), while a suggestive, but non-statistically significant inverse relationship was observed with rMED (HR
= 0.88, 95% CI: 0.68-1.14;
-trend 0.17). Low meat (HR
= 0.81, 95% CI: 0.67-0.99;
-trend = 0.04) and moderate alcohol (HR
= 0.88, 95% CI: 0.75-1.03) intake were related with lower differentiated TC risk.
Our study shows that a high adherence to MD is not strongly related to differentiated TC risk, although further research is required to confirm the impact of MD and, especially, meat intake in TC risk.
Purpose
Chronic inflammation is thought to initiate or promote differentiated thyroid cancer (DTC) and previous studies have shown that diet can modulate this inflammatory process. We aimed to ...evaluate the association of several dietary scores reflecting the inflammatory potential of the diet with DTC risk.
Methods
Within the EPIC cohort, 450,063 participants were followed during a mean period of 14 years, and 712 newly incident DTC cases were identified. Associations between four dietary inflammatory scores the dietary inflammatory index (DII
®
) and two energy-adjusted derivatives (the E-DII
r
and the E-DII
d
), and the Inflammatory Score of the Diet (ISD) and DTC risk were evaluated in the EPIC cohort using multivariable Cox regression models.
Results
Positive associations were observed between DTC risk and the DIIs (HR for 1 SD increase in DII: 1.11, 95%CI: 1.01, 1.23, similar results for its derivatives), but not with the ISD (HR for 1 SD increase: 1.04, 95% CI 0.93, 1.16).
Conclusion
Diet-associated inflammation, as estimated by the DII and its derivatives, was weakly positively associated with DTC risk in a European adult population. These results suggesting that diet-associated inflammation acts in the etiology of DTC need to be validated in independent studies.
The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of ...the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo2,3-bpyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
In a recent study, we showed that the surfactant 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-PEG2000) induced mixed micelles of either threadlike or ...discoidal shape when mixed with different types of lipids. In this study, we have exchanged the PEG−lipid for the more conventional surfactants octaethylene glycol monododecyl ether (C12E8), hexadecyltrimethylammonium bromide (CTAB), and sodium dodecyl sulfate (SDS). Cryo-TEM investigations show that also these surfactants are able to induce the formation of long-lived discoidal micelles. Generally, the preference for either discoidal or threadlike micelles can be tuned by the choice of lipids and environmental conditions in much the same way as observed for the lipid/PEG−lipid system. Our investigation showed, furthermore, that the choice of surfactant may influence the type of mixed micelles formed. It is argued that the formation of discoidal rather than threadlike micelles may be rationalized as an effect of increasing bending rigidity. Our detailed theoretical model calculations show that the bending rigidity becomes significantly raised for aggregates formed by an ionic rather than a nonionic surfactant.
Lysolipid-containing thermosensitive liposomes (LTSL) release their contents instantly when heated to temperatures close to their gel to liquid-crystalline phase transition temperature
(T
C
). We ...have recently shown that during the melting transition these liposomes undergo major morphology changes, including the formation of open liposomes, bilayer discs, and pore-like defects. The hyperthermia-induced release of liposomal contents appears to depend on the presence and accumulation of membrane additives in grain boundaries, which enhance packing defects and, in the case of micelle-forming membrane additives, stabilize the bilayer rim of open liposome structures and transient membrane pores. In the present study, we used the fluorescent label 1-pyrenehexadecanoicacid (PHDA) and a radiolabelled lysolipid as markers for lysolipid membrane distribution and retention, respectively. PHDA dimer formation indicated local PHDA accumulation in cholesterol-free liposomes but not in cholesterol-containing liposomes. When LTSL were incubated at a temperature of 37 °C together with egg-phosphatidylcholine (EPC) multilamellar vesicles (MLVs) approximately 50% of the lysolipids transferred rapidly from LTSL to EPC MLVs. This transfer led to a significant reduction in the amount of carboxyfluorescein released from LTSL upon heating. Our results imply that poor retention of lysolipids in the LTSL membrane could also affect drug release characteristics of LTSL in vivo.
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