Differential effects on inhibition of cholesterol absorption by plant stanol and plant sterol esters in apoE−/− mice

Aims 'Functional foods'; supplemented with plant sterol esters (PSE) and plant stanol esters (PSA) are therapeutic options for the management of hypercholesterolaemia. However, their effects on blood monocytes, endothelial function, atherogenesis, and sterol tissue concentrations are poorly understood. Methods and results Male apoE−/− mice (n= 30) were randomized to three different diets for 6 weeks (n= 10 per group): high-cholesterol (1.25%) western-type diet (WTD), WTD + 2% PSE, and WTD + 2% PSA. Both supplements reduced serum cholesterol. WTD + PSE resulted in increased plant sterol serum concentrations and increased inflammatory Ly-6C(high) monocyte numbers. WTD + PSA increased plant stanol serum concentrations and Ly-6C-monocyte numbers, but decreased vascular superoxide release, lipid hydroperoxides, and inflammatory cytokines in aortic tissue, in plasma, and in circulating monocytes. Despite reduced serum cholesterol concentrations, both supplements impaired endothelial vasodilation compared with WTD. WTD + PSA reduced the development of atherosclerotic lesions compared with WTD alone (12.7 ± 3.7 vs. 28.3 ± 3.5%), and WTD + PSE was less effective (17.5 ± 3.7%). WTD + PSE and WTD + PSA reduced the cholesterol content in the liver, but not in the brain. However, WTD + PSE and WTD + PSA increased plant sterol and plant stanol concentrations in the liver as well as in the brain. Conclusion PSE and PSA supplementation reduced serum cholesterol, but increased plant sterol and plant stanol concentrations. Elevated levels of PSE and PSA were associated with endothelial dysfunction and increased central nervous system depositions. Atherosclerotic lesion retardation was more pronounced in WTD + PSA, coinciding with higher regenerative monocyte numbers, decreased oxidative stress, and decreased inflammatory cytokines compared with WTD + PSE

L1CAM expression in uterine carcinosarcoma is limited to the epithelial component and may be involved in epithelial-mesenchymal transition

Uterine carcinosarcoma (UCS) has been proposed as a model for epithelial-mesenchymal transition (EMT), a process characterized by a functional change facilitating migration and metastasis in many types of cancer. L1CAM is an adhesion molecule that has been involved in EMT as a marker for mesenchymal phenotype. We examined expression of L1CAM in UCS in a cohort of 90 cases from four different centers. Slides were immunohistochemically stained for L1CAM and scored in four categories (0%, 50%). A score of more than 10% was considered positive for L1CAM. The median age at presentation was 68.6years, and half of the patients (53.3%) presented with FIGO stage 1 disease. Membranous L1CAM expression was positive in the epithelial component in 65.4% of cases. Remarkably, expression was negative in the mesenchymal component. In cases where both components were intermingled, expression limited to the epithelial component was confirmed by a double stain for L1CAM and keratin. Expression of L1CAM did not relate to overall or disease-free survival. Our findings suggest L1CAM is either not a marker for the mesenchymal phenotype in EMT, or UCS is not a good model for EMT

Lipoprotein Changes Following Consumption of Lutein-enriched Eggs are Associated with Enhanced Lutein Bioavailability

Abstract Lutein is concentrated in the retina and since it cannot be synthesized by the human body, its uptake depends on nutritional intake. Lutein-enriched eggs are a good lutein source, but whether changes in lipoprotein status following lutein-enriched egg consumption may affect an individual's lutein response is not yet clear. Data from three intervention trials with lutein-enriched eggs or products made from the enriched egg yolks were combined (n=294) and analyzed to investigate the dynamics of the lutein response in relation to lipoprotein levels. Cross sectional correlation was tested at baseline between lutein and lipoprotein profiles in all participants. Subsequently two groups were selected from the combined database whereby individuals receiving lutein-enriched egg yolks (n=137) were compared with controls not receiving eggs (n=117). Significant correlations between blood lutein concentrations and total cholesterol (r=0.309; p<0.001), HDL-C (r=0.246; p<0.001), LDL-C (r=0.241; p<0.001), ApoA1 (r=0.301; p<0.001), and ApoB100 (r=0.199; p<0.005) concentrations, but not with serum triglycerides were found at baseline. Following a three to twelve month intervention, blood lutein concentrations increased from 238 to 463 ng/ml (p<0.001) in the lutein group, whereas levels in controls remained unchanged. The lutein increase in the lutein-enriched egg group correlated significantly with changes in total cholesterol, HDL-C, LDL-C, ApoA1 and ApoB100 concentrations. To conclude, individuals showing the largest lipoprotein increase following egg consumption were also those with the strongest increase in blood lutein concentration. This indicates that therapies directed at altering lipoprotein levels may indirectly affect lutein bioavailability

Expression of CD39 Identifies Activated Intratumoral CD8+T Cells in Mismatch Repair Deficient Endometrial Cancer

Identification of human cancer-reactive CD8+ T cells is crucial for the stratification of patients for immunotherapy and determination of immune-therapeutic effects. To date, these T cells have been identified mainly based on cell surface expression of programmed cell death protein 1 (PD-1) or co-expression of CD103 and CD39. A small subset of CD103- CD39+ CD8+ T cells is also present in tumors, but little is known about these T cells. Here, we report that CD103- CD39+ CD8+ T cells from mismatch repair-deficient endometrial tumors are activated and characterized predominantly by expression of TNFRSF9. In vitro, transforming growth factor-beta (TGF-beta) drives the disappearance of this subset, likely through the conversion of CD103- CD39+ cells to a CD103+ phenotype. On the transcriptomic level, T cell activation and induction of CD39 was associated with a number of tissue residence and TGF-beta responsive transcription factors. Altogether, our data suggest CD39+ CD103- CD8+ tumor-infiltrating T cells are recently activated and likely rapidly differentiate towards tissue residence upon exposure to TGF-beta in the tumor micro-environment, explaining their relative paucity in human tumors

Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients

CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions. Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors. Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery. Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future

Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease

Peer reviewe

The PPARγ Agonist Rosiglitazone Impairs Colonic Inflammation in Mice with Experimental Colitis

Various animal models showed that peroxisome proliferator-activated receptor (PPAR)γ agonists, when given as a gavage shortly preceding colitis induction, protect against inflammatory bowel disease (IBD). We have examined the effects of 16 days rosiglitazone treatment via the diet prior to dextran sodium sulphate (DSS)-induced colitis in mice. After 7 days DSS in the drinking water, rosiglitazone-fed mice had lost significantly more weight than control mice. Rosiglitazone-treated mice had more diarrhea, weight of colon and spleen were increased, and length of colon was decreased. Histology showed that rosiglitazone-treated mice had more severe colitis, mainly caused by more ulceration, crypt loss, and edema. Immunofluorescence showed a loss of tight junction structure Zonula Occludens protein 1 (ZO-1) in colons of rosiglitazone-treated mice as compared to control mice. Also, serum amyloid P component (SAP) concentrations in plasma were increased. However, concentrations of tumor necrosis factor (TNF)-α and interferon (IFN)-γ in colon homogenates, and TNF-α in spleen homogenates were significantly decreased, whereas interleukin (IL)-10 in spleen homogenates was increased. Other cytokines (IL-2, IL-4, IL-6, IL-12p70 and monocyte chemotactic protein (MCP)-1) and myeloperoxidase (MPO) concentrations showed no differences. In conclusion, 16 days pretreatment with rosiglitazone impaired DSS-induced colitis in mice