Longitudinal characterization of a model of chronic allergic lung inflammation in mice using imaging, functional and immunological methods.

The present study investigated the role that imaging could have for assessing lung inflammation in a mouse model of HDM (house dust mite)-provoked allergic inflammation. Inflammation is usually assessed using terminal procedures such as BAL (bronchoalveolar lavage) and histopathology; however, MRI (magnetic resonance imaging) and CT (computed tomography) methods have the potential to allow longitudinal, repeated study of individual animals. Female BALB/c mice were administered daily either saline, or a solution of mixed HDM proteins sufficient to deliver a dose of 12 or 25 µg total HDM protein±budesonide (1 mg/kg of body weight, during weeks 5-7) for 7 weeks. AHR (airway hyper-responsiveness) and IgE measurements were taken on weeks 3, 5 and 7. Following imaging sessions at weeks 3, 5 and 7 lungs were prepared for histology. BAL samples were taken at week 7 and lungs prepared for histology. MRI showed a gradual weekly increase in LTI (lung tissue intensity) in animals treated with HDM compared with control. The 25 µg HDM group showed a continual significant increase in LTI between weeks 3 and 7, the 12 µg HDM-treated group showed a similar rate of increase, and plateaued by week 5. A corresponding increase in AHR, cell counts and IgE were observed. CT showed significant increases in lung tissue density from week 1 of HDM exposure and this was maintained throughout the 7 weeks. Budesonide treatment reversed the increase in tissue density. MRI and CT therefore provide non-invasive sensitive methods for longitudinally assessing lung inflammation. Lung tissue changes could be compared directly with the classical functional and inflammatory readouts, allowing more accurate assessments to be made within each animal and providing a clinically translatable approach.

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

Automatic quantification of changes in bone in serial MR images of joints.

Recent innovations in drug therapies have made it highly desirable to obtain sensitive biomarkers of disease progression that can be used to quantify the performance of candidate disease modifying drugs. In order to measure potential image-based biomarkers of disease progression in an experimental model of rheumatoid arthritis (RA), we present two different methods to automatically quantify changes in a bone in in-vivo serial magnetic resonance (MR) images from the model. Both methods are based on rigid and nonrigid image registration to perform the analysis. The first method uses segmentation propagation to delineate a bone from the serial MR images giving a global measure of temporal changes in bone volume. The second method uses rigid body registration to determine intensity change within a bone, and then maps these into a reference coordinate system using nonrigid registration. This gives a local measure of temporal changes in bone lesion volume. We detected significant temporal changes in local bone lesion volume in five out of eight identified candidate bone lesion regions, and significant difference in local bone lesion volume between male and female subjects in three out of eight candidate bone lesion regions. But the global bone volume was found to be fluctuating over time. Finally, we compare our findings with histology of the subjects and the manual segmentation of bone lesions.

Determination of surface areas, volumes, and lengths of cynomolgus monkey nasal cavities by ex vivo magnetic resonance imaging.

We have used high-resolution three-dimensional magnetic resonance imaging (MRI) to measure the surface area, volume, and length of the nasal cavities of cynomolgus monkeys (10 male, six female) over a range of body weights (1.9-5.3 kg, mean 2.9 kg) and ages (8-45 months, mean 30.0 months). The measurements were carried out ex vivo on formalin-fixed, decalcified nasal cavities filled with water. Mean (standard deviation) values were 30.2 (7.2) cm(2), 2.33 (0.65) cm(3), and 3.34 (0.44) cm, respectively. Linear regression least squares best fits provide the following empirical relationships: Nasal cavity surface area (SA, cm(2)) as a function of body weight (BW, kg): SA = 15.1 + 5.1(BW), R = 0.84 Nasal cavity volume (V, cm(3)) as a function of body weight: V = 1.15 + 0.4(BW), R = 0.74 Nasal cavity length (L, cm) as a function of body weight: L = 2.43 + 0.31(BW), R = 0.84 The left and right sides of the cavity were symmetrical in both males and females and showed little anatomical variation between individuals. The perimeter of the nasal cavity was maximal at about 60% of its extent from the nares. These data can aid in extrapolating nasal dosimetric exposure indices from cynomolgus monkeys (1.9-5.3 kg) to other species.

Longitudinal magnetic resonance imaging quantitation of rat liver regeneration after partial hepatectomy.

This report demonstrates the advantages of using a noninvasive soft tissue imaging technique--magnetic resonance imaging (MRI)--to monitor liver regeneration after 70% partial hepatectomy in the rat in a longitudinal manner. Six animals were scanned prior to and on 6 subsequent occasions up to 9 days after surgical removal of the median and left lateral lobes. Within the observed time frame liver volumes were restored to approximately 88% of presurgery values. Final liver volumes correlated well with postmortem liver weights (R = 0.93). Regeneration is well-quantified empirically by a 4 parameter logistic equation: % Regeneration = 84 - (84/(1 + (Days/2.31)(2.34))) The rate of regeneration was maximal at 1.5 days, which coincided with the maximum increase of Mitotic Index--a measure of cell proliferation, determined in a subsequent study. Pre- and postpartial hepatectomy measurements remove two potentially confounding unknowns--the presurgery liver volume, and the amount of liver actually excised. 3D reconstructions of the liver effectively illustrate the morphological changes associated with the procedure, and the regrowth of liver tissue.