Correlation between nodule volume and diameter in LSL-Kras^G12D;p53^FL/FL (•) and Kras^LA1 (×) models.

<p>(<b>a</b>)<b>.</b> Solid lines indicate cubic fit to the data points. An R² value of 0.93 and 0.81 was obtained for LSL-Kras^G12D;p53^FL/FL and Kras^LA1 models, respectively. Percentage change in nodule volume in the two lung cancer models as a function of nodule diameter (* indicates p<0.05) (b). CT-derived fractional blood volume as a function of nodule diameter (c).</p

Hematoxylin and eosin staining showing characteristics of high-grade lung cancer in LSL-Kras^G12D;^p53FL/FL mice with pleomorphic nuclei (a,b) and low-grade Kras^LA1 lung tumors in Kras^LA1 mice with regular nuclei and minimal cytologic atypia (c,d).

<p>Images were acquired at 10× (a,c) and 40× magnification (c,d). Scale bars: 200 um in a and c; 100 um in b and d.</p

Orthgonal thick slab maximum intensity projection (MIP) images demonstrating visualization of nodule blood supply in the lung cancer models.

<p>The images were acquired immediately after administration of liposomal contrast agent.</p

Representative coronal micro-CT images of LSL-Kras^G12D;p53^FL/FL and Kras^LA1 mice before liposomal contrast-agent injection and at 0 hr, Day 3 and Day 7 post-contrast injection.

<p>Note the differential enhancement of tumors at Day 7 post-contrast time point in the LSL-Kras^G12D;p53^FL/FL lesions only.</p

Differential signal enhancement on day 7 in the two primary lung cancer nodules.

<p>(* indicates p<0.05).</p

Dynamic signal enhancement in (a) blood and (b) nodules, in the two primary lung cancer models. Errors bars represent standard deviations (* indicates p<0.05).

<p>Dynamic signal enhancement in (a) blood and (b) nodules, in the two primary lung cancer models. Errors bars represent standard deviations (* indicates p<0.05).</p

Characterization of Subtle Brain Abnormalities in a Mouse Model of Hedgehog Pathway Antagonist-Induced Cleft Lip and Palate

<div><p>Subtle behavioral and cognitive deficits have been documented in patient cohorts with orofacial clefts (OFCs). Recent neuroimaging studies argue that these traits are associated with structural brain abnormalities but have been limited to adolescent and adult populations where brain plasticity during infancy and childhood may be a confounding factor. Here, we employed high resolution magnetic resonance microscopy to examine primary brain morphology in a mouse model of OFCs. Transient <i>in utero</i> exposure to the Hedgehog (Hh) signaling pathway antagonist cyclopamine resulted in a spectrum of facial dysmorphology, including unilateral and bilateral cleft lip and palate, cleft of the secondary palate only, and a non-cleft phenotype marked by midfacial hypoplasia. Relative to controls, cyclopamine-exposed fetuses exhibited volumetric differences in several brain regions, including hypoplasia of the pituitary gland and olfactory bulbs, hyperplasia of the forebrain septal region, and expansion of the third ventricle. However, in affected fetuses the corpus callosum was intact and normal division of the forebrain was observed. This argues that temporally-specific Hh signaling perturbation can result in typical appearing OFCs in the absence of holoprosencephaly—a condition classically associated with Hh pathway inhibition and frequently co-occurring with OFCs. Supporting the premise that some forms of OFCs co-occur with subtle brain malformations, these results provide a possible ontological basis for traits identified in clinical populations. They also argue in favor of future investigations into genetic and/or environmental modulation of the Hh pathway in the etiopathogenesis of orofacial clefting.</p></div

Volumetric brain abnormalities in cyclopamine-exposed fetuses.

<p>Total brain volumes (inset) were derived following automated skull stripping. Values represent the mean + S.E.M. * p<0.05 compared to the vehicle-exposed control group. For determination of disproportionate differences, the volume of each manually segmented brain region was calculated as a percentage of total brain volume for each animal. Remaining volume includes mid- and hindbrain regions. To illustrate relative changes on the same scale, percent volumes are normalized to mean control values. Values represent the mean ± the S.E.M. ^*p<0.05 compared to the control group.</p

Magnetic resonance microscopy (MRM) enables concurrent visualization of the brain and face of GD17 mouse fetuses.

<p>Forebrain regions, pituitary, and cerebellum were manually segmented from transverse 39 µm MRM sections (A). 3D brain reconstructions were generated by overlaying manually segmented regions with whole-brain masks (B). Reduced opacity of the left cortex and diencephalon allows visualization of the left ventricle, hippocampus, third ventricle, and pituitary. From the same MRM scans, 3D head reconstructions were created, allowing concurrent visualization of the face and brain <i>in situ</i> (C–D). The size of a GD17 mouse fetus can be appreciated when shown in scale with a U.S. penny (E).</p

Cyclopamine-exposed fetuses are not holoprosencephalic.

<p>Along with a vehicle exposed control (A, F, K), representative examples of the cyclopamine-exposed NC (B, G, L), CPO (C, H, M) UL-CLP (D, I, N), BL-CLP (E, J, O), groups are shown. For each example, a coronal MRM section (A–E) showing normal separation between the cerebral hemispheres (arrow) and the secondary palate (arrow head) is shown above a reconstruction of the face and brain (F–J) and a transverse section through the forebrain (K–O). Complete separation of the cerebral hemispheres is evident in each of the reconstructed brains. Transverse sections show normal division of the cerebral cortices with an intact septal region. These images also illustrate deficiency of the pituitary (arrow in G) and olfactory bulbs, and enlargement of the third ventricle (arrow head in M) and septal region in cyclopamine-exposed fetuses. Color-coding in F-O is shown in Fig. 1, where dark red  =  cerebral cortices, light green  =  diencephalon, dark blue  =  septal region, yellow  =  lateral ventricles, orange  =  third ventricle, pink  =  olfactory bulbs, light purple  =  pituitary.</p