The effect of lipids, a lipid-rich ready-to-use therapeutic food, or a phytase on iron absorption from maize-based meals fortified with micronutrient powders.

Background: Ready-to-use-therapeutic foods (RUTFs) high in lipid, protein, and iron are used to treat malnutrition. Lipids increase gastric residence time, which could increase iron absorption, particularly from poorly soluble iron compounds and in combination with phytase.Objectives: The objectives were to 1) assess the effect on iron absorption of a lipid emulsion given 20 min before or together with an iron-fortified maize meal and 2) assess iron absorption from a micronutrient powder (MNP) given with a nutrient-dense RUTF and/or a microbial phytase.Design: A total of 41 women participated in 3 studies. They consumed a maize meal fortified with isotopically labeled ferrous sulfate (FeSO4; study 1) or ferric pyrophosphate (FePP; study 2). In studies 1 and 2, a lipid emulsion was given with or 20 min before the meal. In study 3, with the use of a 2 × 2 factorial design, subjects consumed a maize meal fortified with an MNP containing labeled FeSO4 (MNP) given with an RUTF (MNP+RUTF), with a phytase (MNP+phytase), or both (MNP+RUTF+phytase). Iron absorption was assessed by isotope incorporation in erythrocytes 14 d after the test meals.Results: The lipid emulsion given either before or with the meal significantly increased iron absorption from FePP by 2.55-fold (95% CI: 1.48-, 4.37-fold; P = 0.001) but not from FeSO4 There was a trend to increase iron absorption with the MNP+RUTF meal, which did not reach significance (1.21-fold; 95% CI: 0.92-, 1.61-fold; P = 0.060). The addition of phytase to MNP and MNP+RUTF significantly increased iron absorption by 1.85-fold (95% CI: 1.49-, 2.29-fold; P < 0.001), with no interaction between phytase and RUTF.Conclusions: In iron-fortified maize-based meals, the addition of lipids more than doubles iron absorption from FePP. Our results suggest the possibility of an enhancing effect on iron absorption of lipid-rich RUTFs, but more research is needed to determine this. This trial was registered at clinicaltrials.gov as NCT01991626.

Co-clinical Assessment of Tumor Cellularity in Pancreatic Cancer.

Purpose: Tumor heterogeneity is a hallmark of pancreatic ductal adenocarcinoma (PDAC). It determines tumor biology including tumor cellularity (i.e., amount of neoplastic cells and arrangement into clusters), which is related to the proliferative capacity and differentiation and the degree of desmoplasia among others. Given the close relation of tumor differentiation with differences in progression and therapy response or, e.g., the recently reported protective role of tumor stroma, we aimed at the noninvasive detection of PDAC groups, relevant for future personalized approaches. We hypothesized that histologic differences in PDAC tissue composition are detectable by the noninvasive diffusion weighted- (DW-) MRI-derived apparent diffusion coefficient (ADC) parameter.Experimental design: PDAC cellularity was quantified histologically and correlated with the ADC parameter and survival in genetically engineered mouse models and human patients.Results: Histologic analysis showed an inverse relationship of tumor cellularity and stroma content. Low tumor cellularity correlated with a significantly prolonged mean survival time (PDAClow = 21.93 months vs. PDACmed = 12.7 months; log-rank P < 0.001; HR = 2.23; CI, 1.41-3.53). Multivariate analysis using the Cox regression method confirmed tumor cellularity as an independent prognostic marker (P = 0.034; HR = 1.73; CI, 1.04-2.89). Tumor cellularity showed a strong negative correlation with the ADC parameter in murine (r = -0.84; CI, -0.90- -0.75) and human (r = -0.79; CI, -0.90 to -0.56) PDAC and high preoperative ADC values correlated with prolonged survival (ADChigh = 41.7 months; ADClow = 14.77 months; log rank, P = 0.040) in PDAC patients.Conclusions: This study identifies high tumor cellularity as a negative prognostic factor in PDAC and supports the ADC parameter for the noninvasive identification of PDAC groups. Clin Cancer Res; 23(6); 1461-70. ©2016 AACR.

Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib.

PURPOSE: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models. EXPERIMENTAL DESIGN: DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors. RESULTS: Histologically and biochemically confirmed liver damage resulted in increased (18)F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only. CONCLUSIONS: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.

Nucleic acid delivery to magnetically-labeled cells in a 2D array and at the luminal surface of cell culture tube and their detection by MRI.

The magnetic labeling of living cells has become of major interest in the areas of cell therapy and tissue engineering. Magnetically labeled cells have been reported to allow increased and controlled seeding, tracking, and targeting of cells. In this work, we comprehensively characterize magnetic nanoparticles (MNPs) possessing a magnetite core of about 11 nm, and which are coated with the fluorinated surfactant F(CF2)nCH2CH2SCH2CH2C(O)OLi and 1,9-nonandithiol (NDT) for the nonspecific labeling of human pulmonary epithelial (H441) cells. We achieved a non-specific cell loading of 38 pg Fe/cell. In this work we combine magnetic cell labeling with subsequent genetic modification of the cells with non-viral transfection complexes associated with PEI-Mag2 magnetic nanoparticles upon gradient magnetic field application called magnetofection. The magnetic responsiveness and magnetic moment of the MNP-labeled cells and the magnetic transfection complexes were evaluated by measuring changes in the turbidity of prepared cells suspensions and complexes in a defined magnetic gradient field. The magnetic responsiveness of cells that were loaded with NDT-Mag1 MNPs (20-38 pg Fe/cell) was sufficient to engraft these labeled cells magnetically onto the luminal surface of a culture tube. This was achieved using a solenoid electromagnet that produced a radial magnetic field of 20-30 mT at the seeding area and an axial gradient field of approx. 4 T/m. The MNP-labeled cells were magnetofected in 2D arrays (well plates) and at the luminal surface of cell culture tube. The optimized magnetic pre-labeling of cells did not interfere with, or even increased, the efficiency of magnetofection in both culture systems without causing cell toxicity. Cell loading of 38 pg Fe/cell of NDT-Mag1 MNPs resulted in high transverse relaxivities r2*, thus allowing the MRI detection of cell concentrations that were equivalent to (or higher than) 1.2 microg Fe/ml. Multi-echo gradient echo imaging and R2* mapping detected as few as 1533 MNP-labeled H441 cells localized within a 50 microl fibrin clot and MNP-labeled cell monolayers that were engrafted on the luminal surface of a cell culture tube. Further loading of cells with MNPs did not increase either the magnetic responsiveness of the cells or the sensitivity of MR imaging. In summary, the NDT-Mag1 magnetic nanoparticles provided a high cell-loading efficiency, resulting in strong cell magnetic moments and a high sensitivity to MRI detection. The transfection ability of the labeled cells was also maintained, thereby increasing the magnetofection efficiency.

Effect of ingestion order of the fat component of a solid meal on intragastric fat distribution and gastric emptying assessed by MRI.

PURPOSE: To develop an MRI technique to investigate how varying the ingestion order of nonfat and fat components of a solid meal influences three-dimensional intragastric distribution and gastric emptying (GE). MATERIALS AND METHODS: Eight healthy subjects were studied twice in randomized order. On one occasion (condition F-NF), the fat component (40 g mayonnaise on toast) was served before the nonfat component (270 g pasta, 200 g tomato sauce, 100 mL water); on the other (condition NF-F), the ingestion order was reversed. GE and intragastric distribution of both components were assessed by MRI for 180 minutes. RESULTS: During condition F-NF, GE of fat was significantly faster than during condition NF-F (T(25) [min]: F-NF: 20 +/- 9; NF-F: 40 +/- 7; P < 0.05), a larger amount of fat was observed in the antrum during condition F-NF, and more fat layering occurred. No differences were observed in total GE between the two conditions. CONCLUSION: Meal ingestion order influences GE and intragastric distribution of fat, which can be assessed by MRI techniques, providing new insights into the physiology of gastric processing and intragastric distribution of different meal phases.