Objectives Multicenter oncology trials increasingly include MRI examinations with apparent diffusion coefficient (ADC) quantification for lesion characterization and follow-up. However, the repeatability and reproducibility (R&R) limits above which a true change in ADC can be considered relevant are poorly defined. This study assessed these limits in a standardized whole-body (WB)-MRI protocol. Methods A prospective, multicenter study was performed at three centers equipped with the same 3.0-T scanners to test a WB-MRI protocol including diffusion-weighted imaging (DWI). Eight healthy volunteers per center were enrolled to undergo test and retest examinations in the same center and a third examination in another center. ADC variability was assessed in multiple organs by two readers using two-way mixed ANOVA, Bland-Altman plots, coefficient of variation (CoV), and the upper limit of the 95% CI on repeatability (RC) and reproducibility (RDC) coefficients. Results CoV of ADC was not influenced by other factors (center, reader) than the organ. Based on the upper limit of the 95% CI on RC and RDC (from both readers), a change in ADC in an individual patient must be superior to 12% (cerebrum white matter), 16% (paraspinal muscle), 22% (renal cortex), 26% (central and peripheral zones of the prostate), 29% (renal medulla), 35% (liver), 45% (spleen), 50% (posterior iliac crest), 66% (L5 vertebra), 68% (femur), and 94% (acetabulum) to be significant. Conclusions This study proposes R&R limits above which ADC changes can be considered as a reliable quantitative endpoint to assess disease or treatment-related changes in the tissue microstructure in the setting of multicenter WB-MRI trials. Key Points• The present study showed the range of R&R of ADC in WB-MRI that may be achieved in a multicenter framework when a standardized protocol is deployed. • R&R was not influenced by the site of acquisition of DW images.• Clinically significant changes in ADC measured in a multicenter WB-MRI protocol performed with the same type of MRI scanner must be superior to 12% (cerebrum white matter), 16% (paraspinal muscle), 22% (renal cortex), 26% (central zone and peripheral zone of prostate), 29% (renal medulla), 35% (liver), 45% (spleen), 50% (posterior iliac crest), 66% (L5 vertebra), 68% (femur), and 94% (acetabulum) to be detected with a 95% confidence level.

We evaluated the levels and distribution of hypoxia in 31 human tumors using fluorescent immunohistochemical detection of binding by the 2-nitroimidazole, EF5. Hypoxia was found to be a heterogeneous property of human tumors. Necrosis was usually found adjacent to the highest level of binding in an individual patient's tumor. However, hypoxia often occurred without necrosis. In the group of tumors studied, the most common relationship between blood vessels (PECAM/CD31) and EF5 staining was consistent with diffusion-limited hypoxia; acute hypoxia occurred infrequently. Within a given patient's tumor, there was an inverse correlation between regions of proliferation (Ki-67) and regions of hypoxia. Again, however, when these parameters were examined in a group of patients, the absence of proliferation did not predict the presence of hypoxia. The relationships between hypoxia and other biologic endpoints are complex, but, within a given tumor's spatial relationships, they are in accord with known physiologic principles. Thus, our data emphasize that the relationships between hypoxia and other biologic parameters vary between patients. Necrosis, proliferation, and blood vessel distribution cannot predict the level or presence of hypoxia in an individual patient's tumor.

Background:The dual oxidases (Duox) are involved in hydrogen peroxide generation, which is essential for thyroid hormone synthesis, and therefore they are markers of thyroid function. During inflammation, cytokines upregulate DUOX gene expression in the airway and the intestine, suggesting a role for these proteins in innate immunity. It was previously demonstrated that interleukin-4 (IL-4) upregulates DUOX gene expression in thyrocytes. Although the role of IL-4 in autoimmune thyroid diseases has been studied extensively, the effects of IL-4 on thyroid physiology remain largely unknown. Therefore, a new animal model was generated to study the impact of IL-4 on thyroid function. Methods: Transgenic (Thyr-IL-4) mice with thyroid-targeted expression of murine IL-4 were generated. Transgene expression was verified at the mRNA and protein level in thyroid tissues and primary cultures. The phenotype of the Thyr-IL-4 animals was characterized by measuring serum thyroxine (T4) and thyrotropin levels and performing thyroid morphometric analysis, immunohistochemistry, whole transcriptome sequencing, quantitative reverse transcription polymerase chain reaction, and ex vivo thyroid function assays. Results: Thyrocytes from two Thyr-IL-4 mouse lines (#30 and #52) expressed IL-4, which was secreted into the extracellular space. Although 10-month-old transgenic animals had T4 and thyrotropin serum levels in the normal range, they had altered thyroid follicular structure with enlarged follicles composed of elongated thyrocytes containing numerous endocytic vesicles. These follicles were positive for T4 staining the colloid, indicating their capacity to produce thyroid hormones. RNA profiling of Thyr-IL-4 thyroid samples revealed modulation of multiple genes involved in inflammation, while no major leukocyte infiltration could be detected. Upregulated expression of Duox1, Duoxa1, and the pendrin anion exchanger gene (Slc26a4) was detected. In contrast, the iodide symporter gene Slc5a5 was markedly downregulated resulting in impaired iodide uptake and reduced thyroid hormone levels in transgenic thyroid tissue. Hydrogen peroxide production was increased in Thyr-IL-4 thyroid tissue compared with wild-type animals, but no significant oxidative stress could be detected. Conclusions: This is the first study to show that ectopic expression of IL-4 in thyroid tissue upregulates Duox1/ Duoxa1 and Slc26a4 expression in the thyroid. The present data demonstrate that IL-4 could affect thyroid morphology and function, mainly by downregulating Slc5a5 expression, while maintaining a normal euthyroid phenotype.

Wood density profiles reveal a tree’s life strategy and growth. Density profiles are, however, rarely defined in terms of tissue fractions for wood of tropical angiosperm trees. Here, we aim at linking these fractions to corresponding density profiles of tropical trees from the Congo Basin. Cores of 8 tree species were scanned with X-ray Computed Tomography to calculate density profiles. Then, cores were sanded and the outermost 3 cm were used to semi-automatically measure vessel lumen, parenchyma and fibre fractions using the Weka segmentation tool in ImageJ. Fibre wall and lumen widths were measured using a newly developed semi-automated method. An assessment of density variation in function of growth ring boundary detection is done. A mixed regression model estimated the relative contribution of each trait to the density, with a species effect on slope and intercept of the regression. Position-dependent correlations were made between the fractions and the corresponding wood density profile. On average, density profile variation mostly reflects variations in fibre lumen and wall fractions, but these are species- and position-dependent: on some positions, parenchyma and vessels have a more pronounced effect on density. The model linking density to traits explains 92% of the variation, with 65% of the density profile variation attributed to the three measured traits. The remaining 27% is explained by species as a random effect. There is a clear variation between trees and within trees that have implications for interpreting density profiles in angiosperm trees: the exact driving anatomical fraction behind every density value will depend on the position within the core. The underlying function of density will thus vary accordingly.